AARSKOG-SCOTT SYNDROME (Faciogenital
Dysplasia)

GENE: FGD1 (FYVE, RhoGEF and PH domain-containing 1)
CHROMOSOMAL LOCATION: Xp11.21
MODE OF INHERITANCE: X-linked

Aarskog-Scott syndrome is an X-linked condition characterized by short stature,
hypertelorism, syndactyly, and a characteristic “shawl” scrotum. Cognitive impairment and/or behavioral
disorders occur iconnectn approximately 30-40% of affected individuals. Our laboratory offers DNA sequencing of
all coding exons (exons 1-18) as well as MLPA analysis for the detection of whole-exon or whole-gene deletions
within the FGD1 gene.

This assay may be ordered alone or as part of the X-linked Intellectual Disability
(XLID) panel.

Prenatal testing is available when a variant is known in the family.

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ACUTE MYELOID (or MYELOGENOUS) LEUKEMIA

GENES: FLT3 (fms-related tyrosine kinase 3); NPM1 (nucleophosmin family, member 1)
CHROMOSOMAL LOCATION: 13q12 (FLT3); 5q35 (NPM1)
REGIONS ANALYZED: D835 within FLT3 and NPM1 exon 12 sequencing
INCIDENCE: D835 mutations within the activation loop of the second tyrosin kinase domain (TKD) of FLT3 (FLT3-TKD)
occur in 5%-14% of patients. Approximately 45-60% of patients with chromosomally normal AML carry NPM1 gene
variants.

Acute myeloid leukemia (AML) is the most common childhood malignancy, however AML is
generally an adult-onset condition with an average age of diagnosis of 67 years. Chromosome analysis at the time
of diagnosis provides the most important prognostic information in adults with AML, but 40-50% of patients do
not have clonal chromosomal aberrations. Somatic mutations in chromosomally normal AML have been identified and
include mutations of the tyrosine kinase domain (TKD) of the FLT3 gene. In addition, somatic mutations
have been described in the NPM1 gene.

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ALPHA-THALASSEMIA INTELLECTUAL DISABILITY
SYNDROME (Chudley-Lowry Syndrome, XLMR-Hypotonic Facies Syndrome, Smith-Fineman-Myers MR
Syndrome)

GENE: ATRX (transcriptional regulator ATRX)
CHROMOSOMAL LOCATION: Xq13
MODE OF INHERITANCE: X-linked

Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is characterized by
distinctive craniofacial features, genital anomalies, and severe developmental delays with hypotonia and
intellectual disability. Our laboratory offers DNA sequencing of all coding exons (exons 1-35) as well as MLPA
analysis of exons 1-35 for the detection of whole-exon or whole-gene deletions within the ATRX gene.
This analysis detects up to 95% of pathogenic variants in individuals with a clinical diagnosis of ATRX
syndrome.

This assay may be ordered alone or as part of the X-linked Intellectual Disability
(XLID) panel.

Prenatal testing is available when a variant is known in the family.

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ANEURYSM OSTEOARTHRITIS SYNDROME

GENE: SMAD3 (mothers against decapentaplegic, drosophila, homolog of,
3)
CHROMOSOMAL LOCATION: 15q22.33
MODE OF INHERITANCE: autosomal dominant

Aneurysm osteoarthritis syndrome (also known as Loeys-Dietz syndrome, type III) is a
syndromic form of thoracic aortic aneurysms and dissections characterized by the presence of arterial aneurysms,
arterial tortuosity, early-onset osteoarthritis, and mild craniofacial, cutaneous, and skeletal abnormalities.
Pathogenic variants in the SMAD3 gene have been identified in patients with aneurysm osteoarthritis
syndrome/ Loeys-Dietz syndrome, type III.

Our laboratory offers sequencing of all coding exons in SMAD3, as well as MLPA analysis
for the detection of whole-exon or whole-gene deletions or duplications.

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ANGELMAN SYNDROME

GENE: UBE3A (ubiquitin protein ligase E3A)
CHROMOSOMAL LOCATION: 15q11-q13
MODE OF INHERITANCE: deletion; uniparental disomy; imprinting defects; UBE3A mutations

Angelman syndrome is characterized by severe developmental delay or intellectual
disability, severe speech impairment, gait ataxia, and unique behavior that includes frequent laughing, smiling,
and excitability. Microcephaly and seizures are also common. Angelman syndrome is caused by a deletion or
disruption of the maternal chromosome 15q11-q13 gene region. Our laboratory offers methylation-sensitive MLPA
which detects deletions of the maternal chromosome 15, uniparental disomy of the paternal chromosome 15, and
imprinting defects. Approximately 78% of Angelman syndrome cases are detectable using this assay. In addition,
our laboratory offers sequencing of all coding exons (exons 1-12) of the UBE3A gene which detects an
additional 11% of individuals with a negative methylation result. Thus, molecular genetic testing (methylation
analysis and UBE3A sequence analysis) identifies alterations in approximately 90% of affected
individuals. The remaining 10% of individuals with classic phenotypic features of Angelman syndrome have a
presently unidentified genetic mechanism and thus are not amenable to diagnostic testing. Molecular genetic
testing for Angelman syndrome is recommended for the confirmation of a diagnosis in a patient with or without a
family history of the condition. Karyotyping parents of an affected child and methylation studies of a fetus are
available for prenatal diagnosis. Further studies, including FISH deletion analysis and uniparental disomy
studies (which require parental blood samples), are available and recommended following a positive methylation
test result.

Our laboratory offers a comprehensive Angelman/Angelman-like syndrome panel which includes:

• • Angelman methylation-sensitive MLPA

• • UBE3A sequence analysis

• • SLC9A6 sequence analysis

• • TCF4 analysis

• ZEB2 analysis

Direct testing of any of these genes can be ordered.

(See other individual entries for other CPT codes.)

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ANGELMAN-LIKE SYNDROME (X-linked
syndromic MR- Christianson type)

GENE: SLC9A6 (solute carrier family 9 member 6)
CHROMOSOMAL LOCATION: Xq26.3
MODE OF INHERITANCE: X-linked

Pathogenic variants in the SLC9A6 gene are thought to be responsible for an
X-linked intellectual disability syndrome with Angelman syndrome-like features including microcephaly, seizures,
ataxia, and absent speech. The clinical spectrum of features seem to resemble Angelman syndrome in younger
patients and Christianson syndrome in older patients.

Our laboratory offers DNA sequencing of all coding exons (1-16) of the SLC9A6
gene.

This assay may be ordered alone or as part of the X-linked Intellectual Disability
(XLID) or Angelman / Angelman-like Syndrome panels.

Prenatal testing is available when a variant is known in the family.

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AORTIC VALVE DISEASE

GENE: NOTCH1 (notch 1)
CHROMOSOMAL LOCATION: 9q34.3
MODE OF INHERITANCE: autosomal dominant

Aortic valve disease is the most common form of valvular heart disease. Aortic valve
disease includes aortic valve stenosis (narrowing of the aortic valve opening causing obstruction of flow) and
aortic valve regurgitation (a leakage of the valve backward, into the left ventricle). In extreme cases,
congenital aortic valve stenosis can result in secondary failure of left heart growth, resulting in hypoplastic
left heart syndrome. Bicuspid aortic valve disease, the most common congenital cardiovascular malformation,
leads to an increased risk of aortic aneurysms. Pathogenic variants in the NOTCH1 have been identified
in individuals with nonsyndromic developmental aortic valve anomalies (including bicuspid aortic valve) and
severe valve calcification.

Our laboratory offers sequencing of all 34 coding exons in the NOTCH1 gene.

Prenatal testing is available when a variant has been identified in a family.

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ARX

GENE: ARX (aristaless related homeobox)
CHROMOSOMAL LOCATION: Xp21.3
MODE OF INHERITANCE: X-linked recessive

Pathogenic variants in the ARX gene have been found to cause nonsyndromic
intellectual disability and/or autism, as well as several different forms of syndromic intellectual disability,
including X-linked lissencephaly with abnormal genitalia, X-linked West syndrome, X-linked myoclonic epilepsy
with spasticity and intellectual disability, and Partington syndrome (intellectual disability, ataxia, and
dystonia).

X-linked lissencephaly with abnormal genitalia (XLAG) is characterized by abnormal
brain development resulting in a reduction or lack of folds and grooves in the brain. Individuals with XLAG may
also have agenesis of the corpus callosum. Common features of XLAG include muscle spasticity, hypotonia,
epilepsy, abnormal genitalia, developmental delay, and severe intellectual disability. X-linked West syndrome is
an epilepsy syndrome causing infantile spasms beginning between 3 and 12 months of age and continuing until
about 2-4 years of age, an abnormal EEG (hypsarrhythmia), and intellectual disability. Mild to severe
developmental delay/regression is also commonly seen. Males with X-linked myoclonic epilepsy with spasticity and
intellectual disability (XMESID) have epilepsy, moderate to profound intellectual impairment, and global
developmental delay. Female carriers have hyperreflexia. Individuals with Partington syndrome have intellectual
disability and progressive focal dystonia of the hands beginning in early childhood. Dystonia may also affect
other parts of the body, causing impaired speech and/or an abnormal gait. Other features may include epilepsy
and autism spectrum disorder.

Our laboratory offers sequencing of all coding exons in the ARX, as well as
MLPA analysis for the detection of whole-exon or whole-gene deletions or duplications.

Carrier testing is available for at-risk females (X-inactivation studies are also
recommended and available). Prenatal testing is available for females with an identified variant.

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ASHKENAZI JEWISH PANEL

ATAXIA PANEL

CONDITIONS: SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12,SCA17,
Dentatorubral-Pallidoluysian Atrophy (DRPLA)
GENES: ATXN1 (ataxin 1) –SCA1; ATXN2 (ataxin 2) –SCA2; ATXN3 (ataxin 3) –SCA3; CACNA1A (calcium
channel, voltage-dependent, P/Q type, alpha 1A subunit) –SCA6; ATXN7 (ataxin 7) –SCA7; ATXN8 (ataxin 8)
–SCA8; ATXN10 (ataxin 10) –SCA10; PPP2R2B (protein phosphatase 2, regulatory subunit B, beta)-SCA12; TBP
(TATA-box-binding protein) –SCA17; ATN1 (atrophin-1) –DRPLA
CHROMOSOMAL LOCATIONS: 6p23 (SCA1); 12q24 (SCA2); 14q32.1 (SCA3); 19p13 (SCA6); 3p21.1-p12 (SCA7), 13q21 (SCA8);
22q13 (SCA10); 5q32 (SCA12); 6q27 (SCA17); 12p13.3 (DRPLA)
MODE OF INHERITANCE: autosomal dominant for all

The hereditary ataxias are a group of genetic disorders characterized by slowly
progressive incoordination of gait often associated with poor coordination of hands, speech, and eye movements.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder characterized
by cerebellar ataxia and seizures. The mutation associated with SCA10 is a pentanucleotide repeat (ATTCT)
expansion located in intron 9 of the SCA10 gene. Anticipation has been observed in some families with paternal
transmission of the pentanucleotide repeat expansion. Normal individuals are found to have a range of 10-29
repeats, while affected individuals exhibit allele sizes greater than 800 repeats. Our laboratory offers testing
for the SCA10 pentanucleotide expansion mutation by PCR and Ladder assays.

Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant disorder characterized
by action tremor of the upper extremities progressing to ataxia and other cerebellar and cortical signs. The
mutation associated with SCA12 is a triplet repeat (CAG) expansion located in the promoter region of the SCA12
gene. Normal individuals are found to have a range of 4-32 repeats, while affected individuals exhibit allele
sizes greater than 51 repeats. Our laboratory offers testing for the SCA12 triplet expansion mutation by PCR and
Ladder assays.

Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant disorder characterized
by ataxia, dementia, chorea, and dystonia. The mutation associated with SCA17 is a triplet repeat (CAA/CAG)
expansion located in exon 3 of the SCA17 gene. Normal individuals are found to have a range of 25-42 repeats. A
reduced penetrance range of 43-48 repeats is reported, while affected individuals exhibit allele sizes greater
than or equal to 49 repeats. Our laboratory offers testing for the SCA17 triplet expansion mutation by PCR
analysis.

Dentatorubral pallidoluysian atrophy (DRPLA) is an autosomal dominant disorder
characterized by myoclonus, seizures, ataxia, choreoathetosis and dementia. The mutation associated with DRPLA
is a triplet repeat (CAG) expansion located in exon 5 of the DRPLA gene. Normal individuals are found to have a
range of 6-35 repeats, while affected individuals exhibit allele sizes greater than or equal to 48 repeats. Our
laboratory offers testing for the DRPLA triplet expansion mutation by PCR analysis.

The ataxias listed above have the common characteristics of wide-based unsteady gait,
lack of coordination, dysarthria, scanning and explosive speech, and hyperreflexia. Unless otherwise requested,
all of the above disorders will be tested. If a particular disorder is suspected, gene analysis of that specific
disorder can be done first. If negative, the full ataxia panel will follow. Prenatal diagnosis is available for
families in which the presence of a trinucleotide repeat expansion has been demonstrated. Direct DNA analysis of
the ataxia genes is recommended for symptomatic patients, with or without a family history of ataxia. DNA
analysis of asymptomatic patients with a positive family history of an autosomal dominant ataxia is also
possible. Predictive testing of these patients, including prenatal diagnosis, introduces complex issues and
risks. For this reason we recommend genetic counseling throughout the testing process.

NOTE: Ladder Assays for SCA 2, 7, 8, 10 and 12 are an additional unit of the same CPT Code.

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AUTISM/AUTISM SPECTRUM DISORDER (ASD, 53 gene panel)

Next generation sequencing is performed on the 53 genes known to be causally associated
with autism spectrum disorders (ASD), using the Ion Torrent platform. Approximately 5% of the gene regions are
sequenced individually using a fluorescent Sanger Sequencing technology. The variant detection rate of this
panel exceeds 95%. All pathogenic or likely pathogenic variants are confirmed via Sanger sequencing. The 53
genes tested are listed below.

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AUTISM WITH MACROCEPHALY

GENE: PTEN (phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and
dual-specificity protein phosphatase)
CHROMOSOMAL LOCATION: 10q23.3
MODE OF INHERITANCE: autosomal dominant

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders, in which
patients show deficits in social interaction, impaired communication, repetitive behavior and restricted
interests and activities. It is reported that 25-30% of patients with autism spectrum disorders have a head
circumference greater than the 98th percentile. It is reported that 20% of individuals with autism spectrum
disorders and macrocephaly have PTEN pathogenic variants. Our laboratory offers DNA sequencing of the
promoter region, all coding exons, as well as MLPA analysis of the PTEN gene.

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AUTISM/INTELLECTUAL DISABILITY/SEIZURES

GENES: ARX, SCN1A, CDKL5/STK9
CHROMOSOMAL LOCATION: Xp22.13 (ARX), 2q24.3 (SCN1A), Xp22 (CDKL5/STK9)
MODE OF INHERITANCE: X-linked and autosomal dominant

Infantile spasms occur in at least twenty recognizable disorders including the autism
spectrum disorders group, as well as the Rett syndrome and Rett syndrome-like variant disorder. In the latter
disorder, generalized seizures and myoclonic epilepsy occur within a month or two following birth. The phenotype
also includes intellectual disability and hypsarrhythmia. Our laboratory provides sequencing of the entire
coding region for the ARX, SCN1A, and CDKL5/STK9 genes as well as deletion analysis.

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BLOOM SYNDROME

GENE: BLM (DNA helicase Rec Q protein-like 3)
CHROMOSOMAL LOCATION: 15q26.1
MUTATION ANALYZED: 2281del6bp/ins7bp
CARRIER FREQUENCY: 1 in 111 (Ashkenazi Jewish)
MODE OF INHERITANCE: autosomal recessive

Individuals with Bloom syndrome typically have short stature, pigmentation
abnormalities, and an increased susceptibility to infections, respiratory illnesses, and certain malignancies,
such as leukemia. Bloom syndrome causes chromosomal instability and sister chromatid exchange. The
2281del6bp/ins7bp is present in at least 98% of affected individuals. This assay may be ordered alone or as part
of the Ashkenazi Jewish panel.

Prenatal testing is available when a mutation is known in the family.

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BRANCHIO-OCULO-FACIAL SYNDROME

GENE: TFAP2A (transcription factor AP-2 alpha)
CHROMOSOMAL LOCATION: 6p24
MODE OF INHERITANCE: autosomal dominant

Branchio-Oculo-Facial syndrome (BOFS) is a disorder of the first and second pharyngeal
arches that includes thinned, erythematous cutaneous defects in the cervical or infra- and/or supra-auricular
region, ocular anomalies, nasolacrimal duct obstruction, and characteristic craniofacial features.

Our laboratory offers DNA sequencing of all coding exons as well as the detection of a
whole gene deletion via MLPA analysis of the TFAP2A gene.

Prenatal testing is available when a variant is known in the family.

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BREAST CANCER

GENES: BRCA1, BRCA2
CHROMOSOMAL LOCATION: 17q21 (BRCA1); 13q12.3 (BRCA2)
MUTATIONS ANALYZED (AJ Panel): 185delAG, 5382insC (BRCA1): 6174delT (BRCA2)
INCIDENCE OF THESE MUTATIONS: approximately 2.5% of Ashkenazi Jews
MODE OF INHERITANCE: autosomal dominant

The three mutations above are the most common among the Ashkenazi Jewish population. It
is not known at this time what percentage of familial breast cancer cases are caused by these mutations.
However, for cases in which the family is Ashkenazi Jewish and there is clear evidence of early onset breast
cancer in multiple first- or second-degree relatives, our laboratory can offer screening for these common
BRCA1 and BRCA2 mutations. The 185delAG BRCA1 mutation is referred to as c.68_69delAG
and the 5382insC BRCA1 mutation is referred to as c.5266dupC in the Human Genome Mutation Database
(HGMD). The 6174delT BRCA2 mutation is referred to as c.5946delT in HGMD. Prior to testing, we strongly
urge all patients to have genetic counseling to review their risk of breast and/or ovarian cancer, to discuss
possible findings from screening, and to discuss the relevance of these findings to the management of their
health care. Documentation of cancer reported in the family history is advised. Routine testing of all Jewish
women for these mutations is not recommended.

Our laboratory also offers DNA sequencing of all coding exons as well as MLPA analysis
of the BRCA1 and BRCA2 genes.

Please note that a signed consent form is required prior to the initiation of testing.

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CHROMOSOMAL LOCATION: 16p12.2

MODE OF INHERITANCE: autosomal dominant

Germline loss-of-function variants in the PALB2 gene are known to confer an increased
risk for female and male breast cancer, ovarian cancer (including fallopian tube and primary peritoneal
cancers), and pancreatic cancer.

Our laboratory offers DNA sequencing of all coding exons.

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C9orf72-RELATED NEURODEGENERATIVE DISEASE

GENE: C9ORF72 (chromosome 9 open reading frame 72)
CHROMOSOMAL LOCATION: 9p21.2
MODE OF INHERITANCE: autosomal dominant

The pathogenic GGGGCC repeat expansion in the C9orf72 gene is the most common
known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is a
progressive neurodegenerative disease which affects motor neurons in the brain and spinal cord. Individuals with
ALS experience muscle weakness and atrophy. As the disease progresses, the ability to initiate and control
muscle movement is lost. ALS patients with C9orf72 expansions are more likely to have Parkinsonism and
bulbar findings (dysphagia, dysarthria). Some individuals with repeat expansions in C9orf72 also
develop frontotemporal dementia (FTD). FTD is a progressive disorder which causes atrophy of the frontal and/or
temporal lobes of the brain. Common features of FTD include significant changes in personality and behavior,
impairment or loss of speech, and language difficulties. Individuals with FTD caused by C9orf72
expansions are more likely to have behavioral variant FTD, presenting with psychosis (hallucinations,
delusions).

23 to 30% of those with familial ALS and about 25% of those with familial FTD have a
hexanucleotide repeat expansion (GGGGCC) in a non-coding region of the C9orf72 gene. C9orf72
expansions with greater than 30 repeats are considered pathogenic. It is unclear at this point whether larger
repeat sizes correlate with more severe clinical features and/or earlier age of onset.

C9orf72 repeat expansions have also been observed in some individuals with
late-onset Alzheimer’s disease (AD). Individuals with AD have dementia, typically beginning with subtle memory
loss which becomes progressively more severe. Other features may include confusion, poor judgment, language
difficulties, withdrawal, and hallucinations.

In addition, repeat expansions of the C9orf72 gene have been identified in
patients with Huntington disease-like syndrome (patients with clinical features of Huntington disease [movement,
cognitive, and psychiatric disturbances] and negative testing for the typical genetic cause of HD; also known as
HD phenocopies).

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CADASIL

GENE: NOTCH3
CHROMOSOMAL LOCATION: 19p13.2-p13.1
MODE OF INHERITANCE: autosomal dominant

Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) is characterized by a history of migraine with aura (35% of individuals),
transient ischemic attacks and ischemic stroke (85% of individuals), mood disturbances (20% of individuals),
apathy (40% of individuals), cognitive disturbance progressing to dementia (60-75% of individuals), and diffuse
white matter lesions and subcortical infarcts on neuroimaging. CADASIL is inherited in an autosomal dominant
manner with variable expression in terms of age of onset, severity of clinical symptoms, and progression of the
disease. NOTCH3 is the only gene in which pathogenic variants are known to cause CADASIL.

Our laboratory offers sequencing for 9 selected coding exons in the NOTCH3
gene. Pathogenic variants within these nine exons account for approximately 85-90% of individuals with a
diagnosis of CADASIL.

Prenatal testing is available when a variant has been identified in a family.

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CANAVAN DISEASE

GENE: ASPA (Aspartoacylase)
CHROMOSOMAL LOCATION: 17pter-p13
MUTATIONS ANALYZED: E285A, Y231X, and A305E
CARRIER FREQUENCY: 1 in 40 (Ashkenazi Jewish)
MODE OF INHERITANCE: autosomal recessive

Canavan Disease is a severe progressive genetic disorder of the Central Nervous System
(CNS) that occurs most frequently in children of Ashkenazi (European) Jewish ancestry. Symptoms appear after the
first few months of life and may include macrocephaly, hypotonia, and poor head control. The disease typically
progresses with a lack of muscle development, seizures, optic atrophy, and feeding problems. The large majority
of children with Canavan Disease die before age five. The American College of Obstetrics & Gynecology (ACOG)
recommends carrier screening for couples in which at least one person is of Ashkenazi Jewish ancestry. Direct
DNA analysis is also available for patients who have signs or symptoms suggestive of this disorder. The assay
used detects 98% of mutations in the Ashkenazi Jewish population and approximately 40% of mutations in
individuals with non-Ashkenazi Jewish ancestry. This assay may be ordered alone or as part of the Ashkenazi
Jewish panel.

Prenatal testing is available when a mutation is known in the family.

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CARDIOFACIOCUTANEOUS SYNDROME

GENES: BRAF (B-Raf proto-oncogene serine/threonine-protein kinase); MAP2K1 (MEK1; mitogen-activated
protein kinase kinase 1); MAP2K2 (MEK2; mitogen-activated protein kinase kinase 2); KRAS (GTPase KRas)
CHROMOSOMAL LOCATIONS: 7q34 (BRAF); 12p12.1 (KRAS); MAP2K1 (15q21); MAP2K2 (7q32)
MODE OF INHERITANCE: autosomal dominant, typically de novo

Cardiofaciocutaneous (CFC) syndrome is characterized by short stature, congenital heart
defects, ectodermal abnormalities, and developmental delay/intellectual disability. The clinical features of CFC
syndrome often overlap with those of Noonan and Costello syndromes. Sequence analysis of the BRAF gene
detects missense pathogenic variants in approximately 75%-80% of individuals with a clinical diagnosis of CFC
syndrome. MAP2K1 and MAP2K2 pathogenic variants have been reported in 15%-20% of individuals
with CFC syndrome. Pathogenic variants in KRAS have been found in <5% of individuals with CFC
syndrome. Hence, this above comprehensive analysis performed by our laboratory is expected to detect
approximately 95% of individuals with CFC syndrome.

Testing for CFC syndrome is offered as a comprehensive and simultaneous testing of all
4 CFC genes (most time-effective, with a significantly shorter turn-around-time) or specific testing of any of
these genes can be ordered. Once a variant in the proband is identified, variant-specific testing in relatives
and prenatal diagnosis is available.

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CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A/HNPP

GENE: PMP22 (peripheral myelin protein 22)
CHROMOSOMAL LOCATION: 17p11.2
MODE OF INHERITANCE: autosomal dominant

This disorder is a demyelinating peripheral neuropathy with combined distal muscle
weakness and atrophy with sensory loss and slow nerve conduction. It is often associated with pes cavus foot
deformity and later bilateral foot drop. 70-80% of all CMT1 disorders involve duplication of the PMP22
gene. Deletion of PMP22 results in hereditary neuropathy with liability to pressure palsies (HNPP). Our
laboratory uses MLPA to assess for PMP22 duplications (CMT1A) and PMP22 deletions (HNPP).

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CHARCOT-MARIE-TOOTH DISEASE, TYPES 1B, 2I, 2J

GENE: Myelin protein zero (MPZ)
CHROMOSOMAL LOCATION: 1q22
MODE OF INHERITANCE: autosomal dominant

Charcot-Marie-Tooth disease is a sensorineural peripheral polyneuropathy. Affecting
approximately 1 in 2,500 individuals, CMT is the most common inherited disorder of the peripheral nervous system
(PNS). Autosomal dominant, autosomal recessive, and X-linked forms have been recognized. CMT1 accounts for 50%
of all CMT cases. Approximately 5-10% of CMT1 is type 1B. Our laboratory offers DNA sequencing of all six coding
exons in the MPZ gene, which detects greater than 99% of individuals with CMT1B as well as MLPA
analysis for the detection of whole-exon or whole-gene deletions or duplications within MPZ.

Prenatal diagnosis is available when a variant has been identified in a family.

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CHARGE SYNDROME

GENE: CHD7 (chromodomain helicase DNA-binding protein 7)
CHROMOSOMAL LOCATION: 8q12.1
MODE OF INHERITANCE: autosomal dominant, typically de novo

CHARGE syndrome is characterized by iris colobomas, congenital heart defects, choanal
atresia/stenosis, growth restriction, abnormal genitalia, and ear anomalies/sensorineural deafness. Our
laboratory offers DNA sequencing of all coding exons (exons 2-38) as well as MLPA analysis for the detection of
whole-exon or whole-gene deletions or duplications within CHD7. These analyses detect approximately 65%
of pathogenic variants in individuals with clinically diagnosed CHARGE syndrome.

Prenatal diagnosis is available when a variant has been identified in a family.

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COFFIN LOWRY SYNDROME

GENE: RSK2/RPS6KA3 (ribosomal protein S6 kinase alpha-3)
CHROMOSOMAL LOCATION: Xp22.2-p22.1
MODE OF INHERITANCE: X-linked

Coffin-Lowry syndrome (CLS) is characterized by short stature, typical facial features
(downslanting palpebral fissures and bulbous nasal tip), short, fleshy, tapering fingers, and severe to profound
intellectual disability. Clinical findings in females are variable. Our laboratory offers DNA sequencing of all
coding exons (exons 1-22) as well as MLPA analysis of select exons for the detection of whole-exon or whole-gene
deletions or duplications within RSK2/RPS6KA3. These analyses detect more than 80% of pathogenic
variants in individuals with a clinical diagnosis of Coffin-Lowry syndrome.
This assay may be ordered alone or as part of the X-linked Intellectual Disability (XLID) panel.

Prenatal testing is available when a variant is known in the family.

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CONGENITAL BILATERAL ABSENCE OF THE VAS DEFERENS (CBAVD)

GENE: CFTR (cystic fibrosis transmembrane conductance regulator)
CHROMOSOMAL LOCATION: 7q31
MODE OF INHERITANCE: autosomal recessive

Congenital bilateral absence of the vas deferens (CBAVD), which causes male
infertility, may occur in isolation or as a manifestation of cystic fibrosis. At least one form of the disorder
is caused by pathogenic variants in the cystic fibrosis (CF) transmembrane conductance regulator gene, which is
located on chromosome 7. Most cases of CBAVD without renal agenesis are related to CF, with approximately 75%
having at least 1 detectable CF mutation and 65% having an elevated sweat chloride. Our laboratory offers the
CF100 mutation panel for individuals with CBAVD and their partners.

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CONGENITAL CONTRACTURAL ARACHNODACTYLY (Beals syndrome)

GENE: FBN2 (fibrillin 2)
CHROMOSOMAL LOCATION: 5q23-q31
MODE OF INHERITANCE: autosomal dominant

Congenital contractural arachnodactyly (CCA) is a connective tissue disorder
characterized by a Marfan-like appearance, “crumpled” ear appearance, and multiple contractures of the major
joints. Scoliosis is also often observed. Although patients with CCA may have marfanoid habitus, they do not
exhibit ectopia lentis. Our laboratory offers sequencing of all coding exons (exons 1-65) of the FBN2
gene which detects 27-75% of pathogenic variants in patients with a clinical diagnosis of Congenital
Contractural Arachnodactyly.

Prenatal diagnosis is available when a mutation has been identified in a family.

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CONGENITAL DISORDER OF GLYCOSYLATION, TYPE
1A

GENE: PMM2 (phosphomannomutase 2)
CHROMOSOMAL LOCATION: 16p13
INHERITANCE: autosomal recessive

Congenital Disorder of Glycosylation, Type 1A (PMM2-CDG), is characterized by
developmental delay, weak muscle tone (hypotonia), abnormal distribution of fat, retracted (inverted) nipples,
eyes that do not look in the same direction (strabismus), failure to gain weight, and failure to thrive.
Affected individuals may have distinctive facial features such as a high forehead, triangular face, large ears,
and a thin upper lip. Other symptoms include elevated liver function, seizures, fluid around the heart
(pericardial effusion), and blood clotting disorders. Although symptoms and signs appear during infancy, about
20% of affected infants do not survive the first year of life due to multiple organ failure. Individuals who
live past infancy typically have intellectual disability, reduced sensation and weakness in the arms and legs
(peripheral neuropathy), an abnormal curvature of the spine (kyphoscoliosis), impaired muscle coordination
(ataxia), and joint deformities (contractures). Affected females do not go through puberty due to
hypergonadotropic hypogonadism, which affects hormone production that direct sexual development, while affected
males experience puberty normally but often have small testes.

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CONNECT2: CONNECTIVE TISSUE DISORDERS DNA
SEQUENCING CHIP

The non-profit Center for Human Genetics, Inc. is pleased to announce the availability
of our DNA sequencing chip (CONNECT2) that simultaneously analyzes 47 genes for the connective tissue disorders
listed below. MLPA assays are also available for those genes that have known deletions reported as pathogenic
variants.
Significant clinical overlap exists between many of these disorders, making it even more cost-effective to use
this NEXT GENERATION SEQUENCING PLATFORM. All discovered pathogenic variants will be confirmed by Sanger
sequencing. Uniform coverage exceeds 30X, with supplemental Sanger sequencing improving overall coverage to
greater than 99% of targeted regions.

CONNECT2 is the optimal cost-effective first line test for those with a suspected
dominant undiagnosed hereditary connective tissue disorder or those with a dominant family history of aneurysms.

Connect2 ( 47 genes):

ACTA2, AEBP1, BGN, C1R, C1S, COL1A1, COL1A2, COL2A1, COL3A1, COL4A1, COL4A2, COL5A1, COL5A2, COL9A1, COL9A2, COL9A3,
COL11A1, COL11A2, COL12A1, DCHS1, FBN1, FBN2, FLCN, FLNA, FOXE3, LOX, MAT2A, MFAP5, MYH11, MYLK, NOTCH1, NTM,
PMEPA1, PRKG1, ROBO4, SKI, SLC2A10, SMAD2, SMAD3, SMAD6, TAB2, TGFB2, TGFB3, TGFBR1, TGFBR2, TGFBR3, THSD4

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CONNEXIN 30 (NON-SYNDROMIC DEAFNESS) DELETION ASSAY

GENE: GJB6 (CONNEXIN 30)
CHROMOSOMAL LOCATION: 13q12
MODE OF INHERITANCE: autosomal recessive

Inherited deafness accounts for at least 50% of all hearing loss and is mostly
autosomal-recessive and non-syndromic. The connexin 30 deletion spans over 340 kb, representing the most common
mutation reported in the connexin-30 gene. This deletion is detected in 10-15% of patients with non-syndromic
hearing loss who have one mutation in the connexin-26 gene.

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COSTELLO SYNDROME

GENE: HRAS (GTPase HRas); BRAF (B-Raf proto-oncogene serine/threonine-protein kinase); KRAS (GTPase
KRas)
CHROMOSOMAL LOCATION: 11p15.5 (HRAS); 7q34 (BRAF); 12p12.1 (KRAS)
MODE OF INHERITANCE: autosomal dominant, typically de novo

Costello syndrome is characterized by coarse facial features, failure to thrive in
infancy, short stature, curly/sparse fine hair, facial and/or perianal papillomata, loose soft skin with deep
palmar and plantar creases, and developmental delay/ intellectual disability. Sequence analysis of all coding
exons (exons 1-4) of the HRAS gene detects mutations in approximately 80%-90% of individuals with a clinical
diagnosis of Costello syndrome. Pathogenic variants in KRAS and BRAF have also been reported in individuals with
Costello syndrome.

Testing of Costello syndrome is offered as a comprehensive and simultaneous testing of
all 3 Costello genes (most time-effective, with a significantly shorter turn-around-time) or specific testing of
any of these genes can be ordered. Once a variant in the proband is identified, variant-specific testing in
relatives and prenatal diagnosis is available.

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CTRC-RELATED HEREDITARY PANCREATITIS

GENE: CTRC (chmyotrypsin-C)
CHROMOSOMAL LOCATION: 1p36.21
MODE OF INHERITANCE: multifactorial

Chronic pancreatitis (CP) is a persistent inflammation of the pancreas. Hereditary
pancreatitis (HP) is a form of chronic pancreatitis with the presence of a positive family history (three or
more affected members involving at least two generations) that is inherited in an autosomal dominant fashion
with incomplete penetrance and variable expressivity. Idiopathic pancreatitis (IP) is when neither the
precipitating factors nor a positive family history is known. Chymotrypsin C, encoded by the CTRC gene,
normally functions to prevent premature trypsinogen activation in the pancreas and to permit trypsin degradation
in the gut. Pathogenic variants within this gene have been detected in some patients with IP.

Our laboratory offers DNA sequencing of all coding exons of the CTRC gene.

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CYSTIC FIBROSIS

GENE: CFTR (cystic fibrosis transmembrane conductance regulator)
CHROMOSOMAL LOCATION: 7q31
CARRIER FREQUENCY: 1 in 25
MODE OF INHERITANCE: autosomal recessive

Cystic fibrosis affects epithelia of the respiratory tract, exocrine pancreas,
intestine, male genital tract, hepatobiliary system, and exocrine sweat glands, resulting in a complex
multisystem disease. Pulmonary disease is the major cause of morbidity and mortality in CF. The majority of
cases of cystic fibrosis have a demonstrable mutation in the CFTR gene. Specifically, our panel of 40
mutations detects 98% of mutations in the Ashkenazi Jewish population and up to 90% of mutations in the Northern
European population. Detection rates for individuals of other ethnicities vary. Direct DNA analysis of the
cystic fibrosis gene is recommended for the confirmation of a diagnosis in a patient with or without a family
history of CF. Prenatal diagnosis is available for a family with a confirmed case of cystic fibrosis, or when
there is a suspicion that the fetus is affected (i.e. echogenic bowel). In addition, the American College of
Obstetrics & Gynecology (ACOG) recommends CF carrier screening to all couples in which at least one person
is Caucasian. Cystic fibrosis carrier screening should also be available to couples of other ethnic backgrounds.
If one member of a couple is found to be a CF carrier, then our CF100 mutation panel is recommended for their
partner.

Download our CF Carrier
Screening Brochure.

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DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY
(DRPLA)

GENE: ATN1 (atrophin-1)
CHROMOSOMAL LOCATION: 12p
INCIDENCE: < 1 in 100,000
MODE OF INHERITANCE: autosomal dominant with anticipation

DRPLA is a progressive disorder characterized by ataxia, myoclonus, epilepsy, and
progressive intellectual deterioration in children. In adults, disorder characteristics include ataxia,
choreoathetosis, and dementia or character changes. The mean age of onset is 30 years old (age range 1-62
years). In both familial and sporadic cases of DRPLA, there is a demonstrable trinucleotide repeat expansion
(CAG) believed to be the causative factor of the condition. Direct DNA analysis of the ATN1 gene is
recommended for patients who show symptoms of the condition, with or without a family history of cerebellar
ataxia and dementia. DNA analysis of patients with a positive family history who do not have signs or symptoms
of DRPLA is also available. Predictive testing of these patients, including prenatal diagnosis, introduces
complex issues and risks. For this reason we recommend pre-test genetic counseling for DRPLA.

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DUCHENNE or BECKER MUSCULAR DYSTROPHY
(DMD/BMD)

GENE: Dystrophin
CHROMOSOMAL LOCATION: Xp21.2
MODE OF INHERITANCE: X-linked recessive

An estimated 60-70% of cases of Duchenne/Becker muscular dystrophy have a demonstrable
deletion/duplication of one or more exons in the dystrophin gene. Direct DNA analysis through
deletion/duplication analysis of the dystrophin gene is recommended for confirmation of a diagnosis, in place of
the more invasive method of muscular biopsy confirmation. Carrier testing for at-risk females is available.
Prenatal diagnosis is also available for families in which the presence of a deletion has been demonstrated.

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DNA / LYMPHOBLAST BANKING

We are able to isolate DNA or establish a cell line from either a blood or tissue
sample to be banked in our laboratory for possible future genetic testing. This service requires a consent form
and requisition form complete with the name and address of the individual and/or legal guardian. While the
Center for Human Genetics does not intend to cease operation of the DNA/lymphoblast banking facility, should any
change affecting the storage of samples occur, the Center for Human Genetics will use reasonable efforts to
notify each donating family to determine the disposition of the sample.
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FOXP1

GENES: FOXP1 (forkhead box P1)
CHROMOSOMAL LOCATION: 3p13

Pathogenic variants in the FOXP1 gene have been linked to language impairment,
intellectual disability, autism spectrum disorders (ASD), and motor development delay.

Sequencing of the FOXP1 gene is also available as part of our Autism Spectrum
Disorders panel (53 genes) by next generation sequencing (NGS).

Individuals who are FOXP1 negative may have a FOXP2 pathogenic
variant. This testing is also available at our Center (see FOXP2).

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FOXP2

GENES: FOXP2 (forkhead box P2)
CHROMOSOMAL LOCATION: 7q31.1

Pathogenic variants in the FOXP2 gene have been linked to severe speech and
language impairment, including Developmental Verbal Dyspraxia (DVD, also known as developmental apraxia of
speech), where the affected individual has difficulty expressing himself/herself correctly and consistently. DVD
is a condition that is present from birth and differs from developmental delay of speech, where speech
development occurs more slowly than expected.

Although the severity of DVD can vary from individual to individual, affected children
typically understand language better than they can use it to express themselves. There may be the presence of
other problems including dysarthria (weak or poor control of muscles used for speech); language problems such as
poor vocabulary, incorrect grammar, and difficulty in clearly organizing spoken information; problems with
reading, writing, spelling, or math; coordination or “motor-skill” problems; and chewing and swallowing
difficulties.

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EHLERS-DANLOS SYNDROME TYPE I & II (CLASSIC &
MILD)

GENES: COL5A1 (collagen alpha-1(V) chain)
COL5A2 (collagen alpha-2 (V) chain)
CHROMOSOMAL LOCATION: 9q34.3 (COL5A1); 2q32.2 (COL5A2)
MODE OF INHERITANCE: autosomal dominant

Ehlers-Danlos syndrome, classic type (EDS I/II) is a connective tissue disorder
characterized by skin hyperextensibility and fragility, joint hypermobility, and abnormal wound healing.
Atrophic or ‘cigarette-paper’ scars differentiate EDS types I/II from EDS III, hypermobility type. EDS type I
and II are now thought to represent more severe and milder manifestations of the same disorder, respectively.
Recent comprehensive molecular analysis (Symoens et al. 2012) has demonstrated that over 90% of patients with
classic EDS harbor pathogenic variants in the COL5A1 or COL5A2 genes. Our laboratory offers
DNA sequencing of all 66 coding exons of the COL5A1 and 51 coding exons of the COL5A2 genes.
In addition, MLPA analysis of COL5A1 for detection of whole exon or whole gene deletions or
duplications is available.

Prenatal diagnosis is available when a variant has been identified in a family.

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EHLERS-DANLOS SYNDROME TYPE IV (VASCULAR
TYPE)

GENE: COL3A1 (collagen proα 1(III))
CHROMOSOMAL LOCATION: 2q31
MODE OF INHERITANCE: autosomal dominant

Ehlers-Danlos syndrome, vascular type (EDS IV) is a connective tissue disorder that
represents the most severe form of the Ehlers-Danlos syndromes. The syndrome is typically characterized by thin,
translucent skin, easy bruising, characteristic facial appearance, and arterial, intestinal, and/or uterine
fragility. Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting
signs in 70% of adults. Our laboratory offers DNA sequencing of all coding exons (exons 1-51) as well as MLPA
analysis of select exons for the detection of whole-exon or whole-gene deletions or duplications within the
COL3A1 gene. These analyses detect greater than 98% of pathogenic variants in individuals with
clinically diagnosed EDS type IV.

Prenatal diagnosis is available when a variant has been identified in a family.

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EHLERS-DANLOS SYNDROME TYPE VII A&B (ARTHROCHALASIA TYPE)

GENE: COL1A1 (collagen, type I, alpha 1)
COL1A2 (collagen, type I, alpha 2)
CHROMOSOMAL LOCATION: 17q21.33 (COL1A1), 7q22.1 (COL1A2)
MODE OF INHERITANCE: autosomal dominant

Ehlers-Danlos syndrome, arthrochalasia type (EDS VII) is a connective tissue disorder
characterized by congenital bilateral hip dislocation, severe joint hypermobility, and significant joint
dislocations. There is some overlap between EDS VII and Osteogenesis imperfecta (OI), which is also caused by
pathogenic variants in the COL1A1 and COL1A2 genes. COL1A1 and COL1A2
variants were also seen in patients with EDS I/II (classical type).

Our laboratory offers DNA sequencing of all 52 coding exons of the COL1A1 and
all 52 coding exons of the COL1A2 genes. MLPA analysis of both COL1A1 and COL1A2 for
detection of whole-exon or whole-gene deletions or duplications is also available.

Prenatal diagnosis is available when a variant has been identified in a family.

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EHLERS-DANLOS VARIANT WITH PERIVENTRICULAR
HETEROTOPIA

GENE: FLNA (filamin A, alpha)
CHROMOSOMAL LOCATION: Xq28
MODE OF INHERITANCE: X-linked dominant

Pathogenic variants in FLNA have been identified in rare individuals who have
periventricular nodular heterotopia and also exhibit features of Ehlers-Danlos syndrome (including joint
hypermobility, skin fragility, and/or aortic aneurysms). Periventricular nodular heterotopia is a neuronal
migration disorder in which neurons are located in an abnormal position around the ventricles of the brain. This
disorder is characterized by seizures, typically beginning in adolescence. Affected individuals may have mild
intellectual disability, dyslexia, or developmental delay. The majority of patients are female, as this
condition is typically lethal in males.

Our laboratory offers sequencing of all coding exons in FLNA, as well as MLPA
analysis for the detection of whole-exon or whole-gene deletions or duplications.

Prenatal diagnosis is available when a variant has been identified in a family.

Other diseases caused by pathogenic variants in FLNA:

• • FG Syndrome-2 (OMIM# 300321)

• • Frontometaphyseal dysplasia (OMIM# 305620)

• • Melnick-Needles syndrome (OMIM# 309350)

• • Otopalatodigital syndrome type I (OMIM# 311300)

• • Otopalatodigital syndrome type II (OMIM# 304120)

• Terminal ossesous dysplasia (OMIM# 300244)

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EPILEPSY AND INTELLECTUAL DISABILITY (FEMALE-RESTRICTED)

GENE: PCDH19 (protocadherin 19)
CHROMOSOMAL LOCATION: Xq13.3
MODE OF INHERITANCE: X-linked (sex-limited)

This disorder is characterized by epilepsy and intellectual disability with the
phenotype being restricted only to females.

Our laboratory offers DNA sequencing of all coding exons (1-5) of the PCDH19
gene.

This assay may be ordered alone or as part of the X-linked Intellectual Disability
(XLID) panel.

Prenatal testing is available when a variant is known in the family.

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FACTOR V LEIDEN

GENE: F5 (coagulation factor V)
CHROMOSOMAL LOCATION: 1q21-25
INCIDENCE: 2-8% of the Caucasian population
MODE OF INHERITANCE: autosomal dominant

The most common hereditary blood clotting disorder is due to a specific mutation in the
gene for factor V called the Leiden mutation (Arg506Gln). Individuals who are heterozygous for the Leiden
mutation have a 7-fold increased risk for thrombosis, and those who are homozygous have an 80-fold increased
risk for thrombosis. At risk for carrying the factor V mutation are those with a family history of early onset
stroke, deep vein thrombosis, thromboembolism, pregnancy associated with thrombosis/embolism,
hyperhomocystinemia, and multiple miscarriages. Individuals with the mutation are at increased risk of
thrombosis in the setting of oral contraceptive use, trauma, and surgery. Direct DNA analysis of the Factor V
and prothrombin (see below) mutations are now recommended for at-risk patients because of the importance of
therapy and antithrombotic prophylaxis.

Test also available as part of a thrombophilia panel, also including testing for prothombin and MTHFR.

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FACTOR XI DEFICIENCY (Hemophilia C, Plasma Thromboplastin
Antecedent Deficiency, Rosenthal Syndrome)

GENE: F11 (coagulation factor XI)
CHROMOSOMAL LOCATION: 4q35
MUTATIONS ANALYZED: E117X, F283L
CARRIER FREQUENCY: 1 in 8 (Ashkenazi Jewish)
MODE OF INHERITANCE: autosomal recessive

Inherited factor XI (FXI) deficiency, also called Hemophilia C, is an autosomal
recessive disorder, which is associated with a variable bleeding tendency that usually manifests after trauma or
surgery. Although a rare disorder, the frequency of FXI deficiency is high in certain populations, notably
persons of Ashkenazi descent. This assay may be ordered alone or as part of the Ashkenazi Jewish panel.

Prenatal testing is available when a mutation is known in the family.

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FAMILIAL ADENOMATOUS POLYPOSIS

GENE: APC (adenomatous polyposis coli)
CHROMOSOMAL LOCATION: 5q21-22
MODE OF INHERITANCE: autosomal dominant

Familial adenomatous polyposis (FAP) is a colon cancer predisposition syndrome in which
hundreds to thousands of precancerous colonic polyps develop, beginning at a mean age of 16 years old (range
7-36 years). Without a colectomy, colon cancer is inevitable. The mean age of individulas with untreated colon
cancer is 39 years (range 34-43 years). Extracolonic manifestations may also be present. It has been shown that
approximately 20-25% of all FAP cases represent new pathogenic variants. Our laboratory offers DNA sequencing of
all coding exons (exons 1-15) as well as MLPA analysis for the detection of whole-exon or whole-gene deletions
or duplications within the APC gene. These analyses detect up to 90% of pathogenic variants in
individuals with a clinical diagnosis of FAP.

Prior to testing, we strongly urge all patients to have genetic counseling to review
their risk of cancer, to discuss possible findings from screening, and to discuss the relevance of these
findings to the management of their health care. Documentation of cancer reported in the family history is
advised.

Other phenotypes caused by pathogenic variants in APC:

• • Attenuated FAP

• • Gardner syndrome

• Turcot syndrome

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FAMILIAL DYSAUTONOMIA

GENE: IKBKAP (inhibitor of kappa light polypeptide gene enhancer in
B-cells, kinase complex-associated protein) / IKAP (IKK complex-associated protein)
CHROMOSOMAL LOCATION: 9q31
MUTATIONS ANALYZED: IVS20(+6T->C) and R696P
CARRIER FREQUENCY: 1 in 32 (Ashkenazi Jewish); <1 in 150 (Other) MODE OF INHERITANCE: autosomal recessive

Familial dysautonomia is a progressive neurodegenerative condition that is typically
present at birth. Individuals with this condition may have a variety of sensory/neuronal disturbances and a
decreased life expectancy. This assay detects greater than 98% of individuals with FD mutations. This assay may
be ordered alone or as part of the Ashkenazi Jewish panel.

Prenatal testing is available when a variant is known in the family.

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FAMILIAL HYPERINSULINEMIA

GENE: ABCC8 (ATP-binding cassette, sub-family C (CFTR/MRP), member 8)
CHROMOSOMAL LOCATION: 11p15.1
MUTATIONS ANALYZED: c.4160 delTCT, c.3989-9
CARRIER FREQUENCY: 1:68 (Ashkenazi Jewish)
MODE OF INHERITANCE: autosomal recessive

Familial hyperinsulinemia (or hyperinsulinism, FHI) is characterized by low blood glucose levels (hypoglycemia) due
to the over-secretion of insulin by the pancreas. FHI ranges from mild to severe, even if affected individuals are
in the same family. FHI can manifest as early as within a few hours after birth (neonatal-onset) or in the first
months of life (childhood-onset). Newborns tend to be large for gestational age and usually have severe refractory
(difficult to control) hypoglycemia in the first two days after birth and can have nonspecific symptoms such as
seizures, hypotonia, poor feeding, and apnea. In some cases, resection of the pancreas may be necessary.

This assay may be ordered alone or as part of the Ashkenazi Jewish panel.

Prenatal testing is available when a mutation is known in the family.

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FAMILIAL MEDITERRANEAN FEVER

GENE: MEFV (pyrin)
CHROMOSOMAL LOCATION: 16p13.3
CARRIER FREQUENCY: 1 in 7 (Armenian, Turkish, Arabic); 1 in 28 (Sephardic Jewish)
MODE OF INHERITANCE: autosomal recessive

Familial Mediterranean Fever (FMF) is a genetic disorder characterized by short,
recurrent bouts of fever, accompanied by pain in the abdomen, chest, or joints, and an erysipelas-like erythema.
The four most common mutations reported to cause FMF and one polymorphism/mutation account for approximately 85%
of abnormal alleles in Armenian, Sephardic Jewish, Arabic, or Turkish populations. DNA analysis is recommended
for patients who have signs or symptoms suggestive of this disorder to confirm the clinical diagnosis. Direct
DNA analysis of the MEFV gene is also recommended for carrier screening of couples in which at least
one person is at high risk. Sequencing of exons 1-10 of the MEFV gene is available and detects an
estimated 90-95% of all known pathogenic variants. MLPA is also available for the detection of whole-exon or
whole-gene deletions or duplications within the MEFV gene.

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FANCONI ANEMIA, TYPE C

GENE: FANCC (fanconi anemia, complementation group C)
CHROMOSOMAL LOCATION: 9q22.3
MUTATION ANALYZED: IVS4+4(A>T)
CARRIER FREQUENCY: 1 in 92 (Ashkenazi Jewish); 1 in 300 (Other)
MODE OF INHERITANCE: autosomal recessive

Individuals with Fanconi Anemia type C typically present with multiple congenital
anomalies, followed by pancytopenia in the first decade of life. These individuals are at risk for bone marrow
failure and some cancers. DNA mutation analysis is able to detect approximately 83% of individuals with Fanconi
Anemia type C. This assay may be ordered alone or as part of the Ashkenazi Jewish panel.

Prenatal testing is available when a variant is known in the family.

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FGF10-RELATED DISORDERS
(Lacrimo-Auriculo-Dento-Digital (Levy Hollister); Aplasia of the Lacrimal and Salivary Glands))

GENE: FGF10 (fibroblast growth factor 10)
CHROMOSOMAL LOCATION: 5p13-p12
MODE OF INHERITANCE: autosomal dominant

Pathogenic variants in the FGF10 gene have been found in individuals with
clinical diagnoses of lacrimo-auriculo-dento-digital (LADD), and aplasia of the lacrimal and salivary glands
(ALSG) syndromes. LADD syndrome is characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary
systems, cup-shaped ears, hearing loss, and dental and digital anomalies. ALSG syndrome is characterized by
xerophthalmia and xerostomia which lead to conjunctival scarring, severe dental caries, dental erosion, and
periodontal disease.

Our LADD comprehensive panel includes sequencing of all coding exons and MLPA analysis
of the FGF10 gene. Sequencing of exons 13-19 and MLPA analysis of select exons (2, 3, 5, 7, 13, 14, 15,
and 18) of the FGFR2 gene, as well as sequencing of exon 11 of the FGFR3 gene, are also
available.

Prenatal testing is available when a variant is known in the family.

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FRAGILE X SYNDROME

GENE: FMR1 (fragile X mental retardation 1)
CHROMOSOMAL LOCATION: Xq27.3
INCIDENCE: 1.6-4 in 10,000 affected males; 0.8-2.2 in 10,000 affected females; 1 in 250 carrier females
MODE OF INHERITANCE: X-linked recessive with anticipation

Fragile X syndrome is characterized by moderate intellectual disability in affected
males and mild intellectual disability in affected females. Males may have a characteristic appearance (large
head, long face, prominent forehead and chin, protuding ears), connective tissue findings (joint laxity), and
large testes (postpubertally). Behavioral abnormalities, sometimes including autism spectrum disorder, are also
common. In at least 96% of cases of Fragile-X syndrome there is a trinucleotide repeat expansion (CGG). For most
cases, the allele size of one or both (if female) FMR1 genes is demonstrable by PCR. However, some
cases will require CGG repeat primed PCR to determine allele size. This assay will be performed automatically if
necessary. Direct DNA analysis of the FMR1 gene is recommended for the confirmation of a diagnosis in a
patient with or without a family history of the condition. Testing of individuals with a confirmed family
history is also possible, as is the prenatal diagnosis of a fetus from a family with a known trinucleotide
repeat expansion. Please note that many studies performed for a child who is symptomatic have subsequently been
found to be negative for Fragile-X and positive for a chromosome abnormality. For this reason we would suggest
chromosome analysis concurrently with Fragile-X DNA analysis. About 1 in 250 females are premutation carriers
and are at increased risk to develop premature ovarian failure. Male and female premutation carriers are also at
risk to develop the Fragile-X Tremor Ataxia Syndrome (FXTAS).

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GAUCHER DISEASE

GENE: GBA (acid-beta glucosidase/glucocerebrosidase)
CHROMOSOMAL LOCATION: 1q21-31
MUTATIONS ANALYZED: N370S, 84GG, and L444P
CARRIER FREQUENCY: 1 in 13 (Ashkenazi Jewish); 1 in 150 (Other)
MODE OF INHERITANCE: autosomal recessive

Gaucher disease (GD) consists of several subtypes of varying severity that may involve
the skeletal, Central Nervous System (CNS), and cardiopulmonary systems. In almost all cases of Gaucher disease
there is a mutation in the gene for glucocerebrosidase. Although over 150 mutations have been identified,
sequencing of the three common GD mutations detect approximately 92% of the cases in the Ashkenazi Jewish
population and 55% of the cases in persons of Non-Ashkenazi Jewish ancestry. The American College of Obstetrics
& Gynecology (ACOG) recommends carrier screening for couples in which at least one person is of Ashkenazi
Jewish ancestry. DNA analysis is also available for patients who have signs or symptoms suggestive of this
disorder. This assay may be ordered alone or as part of the Ashkenazi Jewish panel.

Prenatal testing is available when a variant is known in the family.

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GLYCOGEN STORAGE DISEASE TYPE 1A
(von Gierke Disease)

GENE: G6PC (glucose-6-phosphatase)
CHROMOSOMAL LOCATION: 17q21
MUTATIONS ANALYZED: R83C, Q347X
CARRIER FREQUENCY: 1 in 71 (Ashkenazi Jewish)
MODE OF INHERITANCE: autosomal recessive

Glycogen storage disease Type 1A (GSD1A) is a metabolic condition that when untreated,
often results in severe hypoglycemia, seizures, hepato- and renomegaly, growth restriction, and bleeding
tendencies. The R83C mutation is present in approximately 93-100% of affected individuals of Ashkenazi Jewish
descent while the Q347X mutation is a common mutation observed in individuals of Caucasian descent. This assay
may be ordered alone or as part of the Ashkenazi Jewish panel.

Prenatal testing is available when a variant is known in the family.

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HEREDITARY HEMOCHROMATOSIS

GENE: HFE
CHROMOSOMAL LOCATION: 6p21.3
INCIDENCE: 1 in 200 to 1 in 400
CARRIER FREQUENCY: 1/7 to 1/10 Caucasians
MODE OF INHERITANCE: autosomal recessive

Hemochromatosis is characterized by inappropriately high absorption of iron by the
gastrointestinal mucosa, resulting in excessive storage of iron, particularly in the liver, skin, pancreas,
heart, joints, and testes. Abdominal pain, weakness, lethargy, and weight loss are early symptoms of the
disease. Hereditary hemochromatosis (HHC) may be detected using direct DNA analysis. One mutation (C282Y) and
two polymorphisms (H63D, S65C) account for approximately 95% of all hemochromatosis alleles in the HFE
gene. Testing for HHC is available for the detection of affected persons with or without a family history of
this condition. Early detection and presymptomatic diagnosis is important for therapeutic intervention to
prevent multi-organ damage from iron overload. DNA mutation analysis is the only reliable method of carrier
detection for HHC.

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HUNTINGTON DISEASE

GENE: HTT (huntingtin)
CHROMOSOMAL LOCATION: 4p16.3
INCIDENCE: 3-7 per 100,000 (Western European descent)
MODE OF INHERITANCE: autosomal dominant with anticipation

Huntington disease (HD) is a progressive disorder of motor, cognitive, and psychiatric
disturbances. The mean age of onset is 35 to 44 years and the median survival is 15 to 18 years after onset. At
least 98% of both familial and sporadic cases of HD have a demonstrable trinucleotide repeat expansion (CAG).
Direct DNA analysis of the Huntington disease gene is now recommended for patients without a family history of
HD who have signs or symptoms suggestive of this disorder. Predictive testing for presymptomatic patients
introduces complex issues and risks. For this reason, pre-test genetic counseling and neurological evaluation
are strongly recommended in HD.

Please note that a signed consent is required to accompany any samples for predictive
testing.

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INFANTILE SPASMS

GENES: ARX, SCN1A, CDKL5/STK9
CHROMOSOMAL LOCATION: Xp22.13 (ARX), 2q24.3 (SCN1A), Xp22 (CDKL5/STK9)
MODE OF INHERITANCE: X-linked and autosomal dominant

Infantile spasms occur in at least twenty recognizable disorders including the autism
spectrum disorders group, as well as the Rett syndrome and Rett syndrome-like variant disorder. In the latter
disorder, generalized seizures and myoclonic epilepsy occur within a month or two of birth. The phenotype also
includes intellectual disability and hypsarrhythmia. Our laboratory offers sequencing of the entire coding
region for the ARX, SCN1A, and CDKL5/STK9 genes as well as deletion analysis.

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INFERTILITY TESTING (AZOOSPERMIA
DUE TO SPERMATOGENESIS ARREST, INFERTILITY, SUSCEPTIBILITY TO RECURRENT PREGNANCY LOSS)

GENE: SYCP3 (synaptonemal complex protein 3)
CHROMOSOMAL LOCATION: 12q23
MODE OF INHERITANCE: ?autosomal dominant mutations

Spermatogenesis has been shown to arrest in SYCP3-deficient male mice, while
SYCP3-deficient female mice have been shown to have an increased risk of intrauterine death due to
aneuploid oocytes resulting from defective chromosomal segregation. In human studies, pathogenic variants in the
SYCP3 gene were first described in two males with non-obstructive azoospermia and consequent
infertility, thus implicating SYCP3 as a locus required for completion of spermatogenesis in men. More
recently, SYCP3 pathogenic variants have been associated with recurrent pregnancy loss in females.
Thus, SYCP3 testing may be considered in the workup for women with recurrent pregnancy loss, and in
males with non-obstructive azoospermia. Our laboratory offers DNA sequencing of all coding exons (2-9) of the
SYCP3 gene.

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INTELLECTUAL DISABILITY (DOMINANT,
NONSYNDROMIC)

GENE: SYNGAP1 (synaptic Ras GTPase activating protein 1)
CHROMOSOMAL LOCATION: 6p21.3
MODE OF INHERITANCE: autosomal dominant

Recently, de novo pathogenic variants in the SYNGAP1 gene have been found in
patients with moderate to severe mental retardation or autism with severe language impairment, and a lack of
consistent dysmorphic features. Some patients have also been described with seizure disorders.

Our laboratory offers DNA sequencing of all coding exons (1-19) of the SYNGAP1
gene.

Prenatal testing is available when a variant is known in the family.

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INTRACRANIAL ANEURYSM

GENES: NTM (neurotrimin), TGFβR3 (transforming growth factor, beta receptor III)
CHROMOSOMAL LOCATION: 11q25 (NTM); 1p33-p32 (TGFβR3)
MODE OF INHERITANCE: autosomal dominant

Intracranial aneurysms (IA)
are inherited in up to 20% of cases. IA may occur in isolation or in association with certain genetic
syndromes (such as Ehlers-Danlos syndrome or polycystic kidney disease), and may also share a genetic
predisposition with aortic aneurysms. Pathogenic variants in the TGFβR3 gene have been identified
in individuals with intracranial aneurysms. Pathogenic variants in the NTM gene have been
identified in rare families with intracranial and thoracic aortic aneurysms.

Our laboratory offers DNA
sequencing of all coding exons in the NTM and TGFβR3 genes.

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JOUBERT DISEASE

GENE: TMEM216 (transmembrane protein 216)
CHROMOSOMAL LOCATION: 11q13.1
MUTATIONS ANALYZED: R73L
CARRIER FREQUENCY: 1:110 (Ashkenazi Jewish)
MODE OF INHERITANCE: autosomal recessive

Joubert syndrome is characterized by a brain malformation called the molar tooth sign, near the back of the brain.
Symptoms of Joubert syndrome include weak muscle tone (hypotonia) in infancy, which can evolve into difficulty
coordinating movements (ataxia) in early childhood, breathing irregularity in infancy, abnormal eye movements,
delayed development and intellectual disability. Distinctive Joubert syndrome facial features include a broad
forehead, arched eyebrows, droopy eyelids (ptosis), widely spaced eyes, low-set ears, and a triangle-shaped mouth.

The presence of additional signs and symptoms, such as other eye abnormalities (i.e. retinal dystrophy, which can
cause vision loss), kidney disease, liver disease, skeletal abnormalities (i.e. the presence of extra fingers and
toes), and hormone (endocrine) problems, may be classified as Joubert syndrome and related disorders (JSRD)

This assay may be ordered alone or as part of the Ashkenazi Jewish panel.

Prenatal testing is available when a mutation is known in the family.

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KABUKI SYNDROME

GENE: KMT2D/MLL2 (myeloid/lymphoid or mixed-lineage leukemia 2)
CHROMOSOMAL LOCATION: 12q13.12
MODE OF INHERITANCE: typically sporadic, however autosomal dominant inheritance has been observed

Kabuki syndrome is a multiple congenital anomaly condition characterized by a
characteristic facial appearance (long palpebral fissures with eversion of the lateral third of the lower
eyelids, arched eyebrows, a broad nasal tip, a high arched palate, large prominent earlobes), persistent
fingertip pads, short stature, variable skeletal and organ defects, immunodeficiency, and varying degrees of
intellectual impairment. Recently, pathogenic variants within the KMT2D/MLL2 gene have been detected in
patients with Kabuki syndrome. Sequence analysis of all coding exons of the KMT2D/MLL2 gene is thought
to detect pathogenic variants in up to 76% of patients with a clinical diagnosis of Kabuki syndrome. Our
laboratory offers DNA sequencing of all fifty-four coding exons of the KMT2D/MLL2 gene. In addition,
MLPA analysis of select exons for the detection of whole-exon or whole-gene deletions or duplications in the
KMT2D/MLL2 gene is available.

Prenatal diagnosis is available when a variant has been identified in a family.

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KABUKI SYNDROME

GENE: KDM6A (lysine demethylase 6A)
CHROMOSOMAL LOCATION: Xp11.3
MODE OF INHERITANCE: typically sporadic

The KDM6A gene is the second gene identified that results in Kabuki syndrome
in affected males and females when a point pathogenic variant or deletion is demonstrated. The detection rate in
these Kabuki syndrome patients that are KMT2D/MLL2 negative has been determined to be between 9-13%.
Our laboratory offers DNA sequencing of all 29 coding exons of the KDM6A gene. In addition, MLPA
analysis of select exons for the detection of whole – exon or whole gene deletions or duplications in the
KDM6A gene is available.

Prenatal diagnosis is available when a variant has been identified in a family.

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KENNEDY DISEASE (Spinal Bulbar Muscular Atrophy, SBMA)

GENE: AR (androgen receptor)
CHROMOSOMAL LOCATION: Xq11-q12
INCIDENCE: 1/50,000
MODE OF INHERITANCE: X-linked

Kennedy Disease, also known as Spinal and Bulbar Muscular Atrophy (SBMA), is a
degenerative neuromuscular disorder that affects proximal muscles involved in voluntary activities such as
walking, head and neck control and swallowing. SBMA is a rare adult-onset subtype of Spinal Muscular Atrophy.
Individuals with SBMA exhibit a demonstrable trinucleotide repeat expansion (CAG) in exon 1. Direct DNA analysis
of the SBMA gene is now recommended for symptomatic patients with or without a family history of the disorder.
DNA analysis of patients with a positive family history who do not have signs or symptoms of SBMA is also
possible. Predictive testing of these patients, including prenatal diagnosis, introduces complex issues and
risks. For this reason we recommend pre-test genetic counseling for SBMA.

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LEOPARD SYNDROME

GENE: PTPN11 (tyrosine-protein phosphatase non-receptor type 11)
RAF1 (RAF proto-oncogene serine/threonine-protein kinase)
BRAF (B-Raf proto-oncogene serine/threonine-protein kinase)
CHROMOSOMAL LOCATION: 12q24.1 (PTPN11); 3p25 (RAF1), 7q34 (BRAF)
MODE OF INHERITANCE: autosomal dominant

LEOPARD syndrome is characterized by multiple lentigines, EKG abnormalities, ocular
hypertelorism, pulmonic stenosis, abnormal genitalia, growth restriction, and sensorineural deafness. There is
clinical overlap with features of Noonan syndrome (facial anomalies, distinct congenital heart defects, pectus
deformity, hearing loss and short stature). Pathogenic variants in the PTPN11 gene have been identified
in approximately 90% of patients with the clinical diagnosis of LEOPARD syndrome. Missense pathogenic variants
in RAF1 are thought to account for approximately 3% of LEOPARD syndrome. Pathogenic variants in
BRAF have also been associated with LEOPARD syndrome. Prenatal diagnosis is available when a variant
has been identified in a family.

Testing of LEOPARD syndrome is offered as a comprehensive and simultaneous testing of 3
LEOPARD genes (most time-effective, with a significantly shorter turn-around-time) or specific testing of any of
these genes can be ordered. Once a variant in the proband is identified, variant-specific testing in relatives
and prenatal diagnosis is available.

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LIPOAMIDE DEHYDROGENASE DEFICIENCY

GENE: DLD
CHROMOSOMAL LOCATION: 7q31-q32
MUTATIONS ANALYZED: G229C, c.104dupA
CARRIER FREQUENCY: 1:107 (Ashkenazi Jewish)
MODE OF INHERITANCE: autosomal recessive

Dihydrolipoamide dehydrogenase deficiency can lead to a buildup of lactic acid in tissues (lactic acidosis),
decreased muscle tone (hypotonia), extreme tiredness (lethargy), liver problems ranging from an enlarged liver
(hepatomegaly) to liver failure, excess ammonia in the blood (hyperammonemia), buildup of ketones in the body
(ketoacidosis), or low blood sugar (hypoglycemia). Signs and symptoms of this condition usually appear in episodes
that may be triggered by stresses on the body (i.e. fever, injury). Many infants with this condition do not survive
the first few years of life due to the severity of the episodes. Affected individuals who do survive past early
childhood often have delayed growth and neurological problems, including intellectual disability, muscle stiffness
(spasticity), difficulty coordinating movements (ataxia), and seizures.

This assay may be ordered alone or as part of the Ashkenazi Jewish panel.

Prenatal testing is available when a mutation is known in the family.

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LOEYS-DIETZ SYNDROME

GENE: TGFβR1 (transforming growth factor-beta receptor, type
I); TGFβR2 (transforming growth factor-beta receptor, type II); SMAD2 (mothers against decapentaplegic,
drosophila, homolog of 2); SMAD3 (mothers against decapentaplegic, drosophila, homolog of, 3); TGFβ2
(transforming growth factor, beta-2); TGFβ3 (transforming growth factor, beta-3)
CHROMOSOMAL LOCATION: 9q33-34 (TGFβR1); 3p22 (TGFβR2); 18q21.1 (SMAD2); 15q22.33 (SMAD3); 1q41 (TGFβ2); 14q24
(TGFβ3)
MODE OF INHERITANCE: autosomal dominant

Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular
findings (dilatation/ dissection of the aorta, arterial aneurysms, tortuosity), skeletal abnormalities, and
craniofacial or cutaneous abnormalities. Although patients with LDS may have marfanoid habitus, they typically
do not exhibit ectopia lentis or arachnodactyly. LDS is a clinical continuum including LDS1 (about 75% of
affected individuals; craniofacial abnormalities present) and LDS2 (about 25% of affected individuals; minimal
or absent craniofacial findings). Approximately 70% of individuals with a clinical diagnosis of LDS may have a
pathogenic variant in TGFβR2, about 20% in TGFβR1, about 5% in SMAD3, and about 1% in
TGFβ2. Pathogenic variants have been identified in TGFβ2 that result in a phenotype similar to
those patients with pathogenic variants in TGFβR1 or TGFβR2.  Tall stature, pectus deformity,
club foot, aortic root aneurysm, and mitral valve insufficiency are common features with pathogenic variants in
TGFβ2 (LDS4).  Pathogenic variants in the SMAD2 gene have been implicated in the pathogenesis
of arterial aneurysms and dissections and may result in phenotypic features that overlap Loeys-Dietz syndrome. 
Pathogenic variants in SMAD3 have been identified in patients with a clinical diagnosis of LDS3, and in
patients with a syndromic form of aortic aneurysms and dissections with early onset osteoarthritis. Pectus
deformity, aortic root aneurysm, arterial tortuosity, and early dissection are common features with pathogenic
variants in SMAD3. Most recently, pathogenic variants in TGFβ3 have been associated with a clinical
diagnosis of LDS5 (Rienhoff syndrome), which is characterized by aortic aneurysms involving the thoracic and/or
abdominal aorta, with risk of dissection and rupture, and sometimes, cleft palate, bifid uvula, mitral valve
disease, skeletal overgrowth, cervical spine instability, and clubfoot deformity.

Our laboratory offers sequencing of all coding exons in TGFβR1,
TGFβR2, SMAD2, SMAD3, TGFβ2, and TGFβ3, as well as MLPA analysis
for the detection of whole-exon or whole-gene deletions or duplications within all exons of TGFβ2 and
SMAD3, and select exons of TGFβR1 and TGFβR2. These analyses detect approximately 96%
of pathogenic variants in individuals with clinically diagnosed Loeys-Dietz syndrome.

MLPA analysis is run concurrently with sequence analysis, however can be performed in a
reflex fashion if specifically requested.

Prenatal diagnosis is available when a variant has been identified in a family.

Other diseases caused by pathogenic variants in TGFβR1:

• • Loeys-Dietz aortic aneurysm (OMIM# 609192)

• • Familial thoracic aortic aneurysms (OMIM# 608967)

• Furlong syndrome (OMIM# 610168)

Other diseases caused by pathogenic variants in TGFβR2:

• • Loeys-Dietz aortic aneurysm (OMIM# 609192)

• Familial thoracic aortic aneurysms (OMIM# 608967)

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LYNCH SYNDROME/HEREDITARY NON-POLYPOSIS
COLORECTAL CANCER (HNPCC)

GENE: MLH1 (DNA mismatch repair protein Mlh1)
MSH2 (DNA mismatch repair protein Msh2)
MSH6 (DNA mismatch repair protein Msh6)
TACSTD1 (EPCAM) (Tumor-Associated Calcium Signal Transducer 1)
PMS2 (DNA mismatch repair gene PMSL2)
CHROMOSOMAL LOCATION: 3p21.3 (MLH1); 2p22-p21 (MSH2); 2p16 (MSH6); 2p21 (TACSTD1); 7p22 (PMS2)
MODE OF INHERITANCE: autosomal dominant

Lynch syndrome/Hereditary non-polyposis colorectal cancer (HNPCC) is a cancer
predisposition syndrome caused by pathogenic variants in four genes involved in the mismatch repair pathway
(MLH1, MSH2, MSH6, and PMS2). In addition, deletions in the TACSTD1
(EPCAM) gene may lead to transcriptional interference of the MSH2 gene. Lynch syndrome is
thought to account for approximately 1%-3% of colon cancers and 0.8%-1.4% of endometrial cancers. Individuals
with Lynch syndrome have an up to 80% lifetime risk for colon cancer, with an average age of diagnosis of 44
years old. Women with Lynch syndrome have an up to 20%-60% lifetime risk for endometrial cancer, with an average
age of diagnosis of 46 years old. Germline variants in MLH1 and MSH2 account for approximately
90% of detected pathogenic variants in families with Lynch syndrome. Pathogenic variants in MSH6 have
been reported in approximately 7%-10% of families with Lynch syndrome. Our laboratory offers DNA sequencing and
MLPA analysis of all coding exons of the MLH1, MSH2, MSH6, and PMS2 genes.
DNA sequence analysis detects approximately 90-95% of Lynch syndrome pathogenic variants in the MLH1
gene, 50-80% of Lynch syndrome pathogenic variants in the MSH2 gene, and an unknown number of Lynch
syndrome pathogenic variants in the MSH6 and PMS2 genes. Deletion analysis via MLPA detects
approximately 5-10% of pathogenic variants in the MLH1 gene, 20-50% of pathogenic variants in the
MSH2 gene, and an unknown number of pathogenic variants in the MSH6 and PMS2 genes.
Deletion analysis of exons 3 and 9 via MLPA detects a currently unknown number of pathogenic variants in the
TACSTD1 (EPCAM) gene.

Prior to testing, we strongly urge all patients to have genetic counseling to review
their risk of cancer and a hereditary predisposition to cancer based on personal medical history and family
history, as well as to discuss the relevance of these findings to the management of their health care.
Documentation of cancer reported in the family history is advised.

Other phenotypes caused by pathogenic variants in Lynch syndrome genes:

• • Muir-Torre syndrome

• Turcot syndrome

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MAPLE SYRUP URINE DISEASE TYPE 1B
(E1b subunit gene, MSUD type 1B)

GENE: BCKDHB (2-oxoisovalerate dehydrogenase beta subunit)
CHROMOSOMAL LOCATION:6p22-p21
MUTATIONS ANALYZED: G278S, R183P, E372X
CARRIER FREQUENCY: 1 in 81 (Ashkenazi Jewish)
MODE OF INHERITANCE: autosomal recessive

MSUD is a neurodegenerative metabolic condition that when untreated, often results in
poor feeding, lethargy, intellectual disability, physical disabilities, coma and death. The G278S mutation is
typically associated with the intermediate phenotype, while the E372X mutation is typically associated with the
classic phenotype. This assay may be ordered alone or as part of the Ashkenazi Jewish panel.

Prenatal testing is available when a mutation is known in the family.

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MARFAN SYNDROME

GENE: FBN1 (fibrillin 1)
CHROMOSOMAL LOCATION: 15q21.1
MODE OF INHERITANCE: autosomal dominant

Marfan syndrome (MFS) is a connective tissue disorder that affects multiple organ
systems with primary involvement of the skeletal, ocular and cardiovascular systems. A diagnosis is often based
on the presence of a family history (75% of individuals have an affected parent) and clinical findings. Up to
90% of individuals with a clinical diagnosis of MFS have FBN1 pathogenic variants. Our laboratory
offers sequencing of all coding exons (exons 2-66) as well as MLPA analysis for the detection of whole-exon or
whole-gene deletions or duplication within FBN1. This analysis detects approximately 70-93% of
pathogenic variants in patients with a clinical diagnosis of Marfan syndrome.

MLPA analysis is run concurrently with sequence analysis, however can be performed in a
reflex fashion, if specifically requested.

Prenatal diagnosis is available when a variant has been identified in a family.

Individuals who are FBN1 negative, may have a TGFβR2 pathogenic
variant (up to 21%) or a TGFβR1 pathogenic variant (up to 4%). This testing is also available at our
Center (see Loeys-Dietz syndrome).

Other conditions caused by pathogenic variants in FBN1:

• • Shprintzen-Goldberg Craniosynostosis Syndrome
    (OMIM# 182212)

• • Weill-Marchesani Syndrome (OMIM# 608328)

• • MASS Syndrome (OMIM# 604328)

• • Isolated Ectopia Lentis (OMIM# 129600)

• Familial thoracic aortic aneurysms (OMIM# 608967)

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MATERNAL CELL CONTAMINATION
STUDIES

Maternal cell contamination (MCC) studies ensures that results from testing prenatal
samples, such as amniotic fluid and chorionic villus sample (CVS), are of fetal origin, ensuring accurate
prenatal genetic testing, reporting, and decision-making. The Center for Human Genetics offers analysis at 15
loci to rule out MCC.
Please contact the Center for Human Genetics prior to sending any prenatal samples.

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MED12 RELATED DISORDERS (FG
syndrome type 1 (Opitz-Kaveggia); Lujan-Fryns (X-linked MR with Marfanoid habitus), X-linked Ohdo syndrome)

GENE: MED12 (mediator of RNA polymerase II transcription, subunit 12
homolog)
CHROMOSOMAL LOCATION: Xq13
MODE OF INHERITANCE: X-linked

Pathogenic variants in the MED12 gene have been found in individuals with
clinical diagnoses of FG syndrome (Opitz-Kaveggia), Lujan-Fryns syndromes and X-linked Ohdo syndrome. FG
syndrome is characterized by typical facial features, intellectual disability, macrocephaly, abnormalities of
the corpus callosum, imperforate anus, and hypotonia. Individuals with FG syndrome are also thought to have a
distinctive behavioral phenotype of hyperactivity and excessive talkativeness. Lujan-Fryns syndrome is
characterized by tall stature, thin body habitus, macrocephaly, abnormalities of the corpus callosum,
hypernasality, hyperextensible digits, and intellectual disability. Ohdo syndrome is characterized by
intellectual disability, blepharophimosis and facial coarsening. Dental hypoplasia, deafness and cryptorchidism
are common features.

Our laboratory offers DNA sequencing of all coding exons (1-45) of the MED12
gene.

This assay may be ordered alone or as part of the X-linked Intellectual Disability
(XLID) panel.

Prenatal testing is available when a variant is known in the family.

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GENE: CDKN2A (p16: cyclin-dependent kinase inhibitor 2A)
CHROMOSOMAL LOCATION: 9p21
MODE OF INHERITANCE: autosomal dominant

Multiple primary melanomas are not uncommon, however ~10% of melanoma is hereditary.
Pathogenic variants in the CDKN2A gene are thought to account for up to 40% of hereditary melanoma
cases. Individuals with Familial Melanoma have a genetic predisposition to develop multiple clinically abnormal
and histologically dysplastic pigmented nevi. Their age at onset tends to be earlier than in individuals with
sporadic (non-hereditary) melanoma. Affected individuals also are at increased risk to develop ocular melanoma,
and some families show a predisposition to pancreatic cancer. Our laboratory offers sequencing of all coding
exons (exons 1-3) as well as MLPA analysis for the detection of whole-exon or whole-gene deletions or
duplications within the CDKN2A gene. Prior to testing, we strongly urge all patients to have genetic
counseling to review their risk of melanoma, to discuss possible findings from screening, and to discuss the
relevance of these findings to the management of their health care. Documentation of cancer reported in the
family history is advised.

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METHYLENETETRAHYDROFOLATE
REDUCTASE (MTHFR)

GENE: MTHFR (methylenetetrahydrofolate reductase; c.665C>T)
CHROMOSOMAL LOCATION: 1p36.3
MODE OF INHERITANCE: autosomal recessive

Genetic risk factors are involved in the predisposition of individuals to venous
thrombosis. These include increased plasma homocysteine levels, which are associated with a nucleotide variant
in the methylenetetrahydrofolate reductase (MTHFR) gene. The MTHFR 665C>T (previously
677C>T) thermolabile variant results in a decreased utilization of folate, which is a cofactor required for
homocysteine remethylation. Homozygocity for the MTHFR 665C>T variant is associated with mild to
moderate hyperhomocysteinemia with an increased risk for premature cardiovascular disease. Direct DNA analysis
of the MTHFR gene is available for all individuals with a family history of venous thrombosis or a
known MTHFR variant.

Test also available as part of a thrombophilia panel, also including testing for Factor
V Leiden and prothrombin.

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MITOCHONDRIAL DISORDERS

Mitochondrial disorders are a heterogeneous group of diseases that are caused by
abnormalities in the mitochondrial respiratory chain. Common clinical features of mitochondrial disease include
ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural
deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. The central nervous system findings are
often fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity.
Mitochondrial disorders may be caused by defects of nuclear DNA or mtDNA. Nuclear gene defects may be inherited
in an autosomal dominant or autosomal recessive manner. MtDNA defects are transmitted by maternal inheritance.
Many patients display a cluster of clinical features that fall into a specific clinical syndrome; however, there
is often considerable clinical variability. Our laboratory offers testing for nine common mutations, including
A3243G and T3271C in the tRNA-leu (UUR) gene, which cause MELAS (Mitochondrial Encephalopathy, lactic acidosis
and stroke-like episodes), A8344G and T8356C in the tRNA-lys gene, which causes MERRF (myoclonic epilepsy and
ragged red fiber), G3460A, and G11778A mutations, which cause LHON (Lebers hereditary optic neuropathy), and
T8993C and T8993G in subunit 6 of the ATPase gene, which cause NARP (neuropathy, ataxia and retinitis
pigmentosa), which are also responsible for approximately 10% of Leigh syndrome cases. In addition, a common
deletion of mtDNA, which causes Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO)
or Pearson marrow-pancreas syndrome is also examined. These analyses can be ordered separately or as a panel. In
addition, analysis of all 37 mitochondrial genes is now available. Prenatal genetic testing and interpretation
of test results for mtDNA disorders are difficult because of mtDNA heteroplasmy.

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MOWAT-WILSON SYNDROME

GENE: ZEB2 (zinc finger E-box binding homeobox 2)
CHROMOSOMAL LOCATION: 2q22.3
MODE OF INHERITANCE: autosomal dominant, typically de novo

Mowat-Wilson syndrome (MWS) is characterized by microcephaly, abnormalities of the
corpus callosum, growth restriction, chronic constipation and/or Hirschsprung disease, and congenital heart
defects. Moderate to severe cognitive impairment is also a cardinal feature of the syndrome. The characteristic
facial gestalt of MWS evolves with age. In young children, the characteristic features include a high forehead,
deep-set eyes, a broad nasal bridge, open mouth with a full lower lip, and posteriorly rotated ears with
uplifted earlobes and a central depression. In older individuals, the chin and nasal tip becomes more prominent
and the face elongates. Because of its phenotypic and behavioral overlap (patients with MWS often have a
wide-based ataxic gait, smiling face, and delayed/absent speech) MWS is an important differential diagnosis of
Angelman syndrome.

Sequence analysis of all coding exons of the ZEB2 gene is thought to detect
pathogenic variants in approximately 80% of patients with a clinical diagnosis of MWS. Approximately 15% of
patients will have large entire gene deletions, whilst an additional 2% will have exonic gene deletions that can
be detected by MLPA analysis.

Our laboratory offers DNA sequencing of all nine coding exons, as well as MLPA analysis
for the detection of whole-exon or whole-gene deletions within the ZEB2 gene.

Prenatal diagnosis is available when a variant has been identified in a family.

Our laboratory offers a comprehensive Angelman / Angelman-like Syndrome panel which
includes:

• • Angelman methylation studies

• • UBE3A sequence analysis

• • SLC9A6 sequence analysis

• • TCF4 analysis

• ZEB2 analysis

Direct testing of any of these genes can be ordered.

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MUCOLIPIDOSIS TYPE IV

GENE: MCOLN1 (mucolipin-1)
CHROMOSOMAL LOCATION:19p13.3-p13.2
MUTATIONS ANALYZED: IVS3-2 A>G, Deletion exons 1-7
CARRIER FREQUENCY: 1 in 122 (Ashkenazi Jewish)
MODE OF INHERITANCE: autosomal recessive

Mucolipidosis type IV is a neurodegenerative lysosomal storage disorder characterized
clinically by severe psychomotor impairment and ophthalmologic abnormalities. The splice mutation and partial
gene deletion account for approximately 95% of mutations in individuals with Ashkenazi Jewish descent. This
assay may be ordered alone or as part of the Ashkenazi Jewish panel.

Prenatal testing is available when a variant is known in the family.

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MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN1)
SYNDROME

GENE: MEN1 (menin)
CHROMOSOMAL LOCATION: 11q13
MODE OF INHERITANCE: autosomal dominant

Multiple endocrine neoplasia type 1 (MEN1) syndrome includes a combination of endocrine
tumors (parathyroid tumors, pituitary tumors, tumors of the gastro-entero-pancreatic tract, and adrenocortical
tumors) and non-endocrine tumors (facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and
leiomyomas). MEN1 syndrome is inherited in an autosomal dominant manner and approximately 10% of cases are due
to de novo pathogenic variants. Our laboratory offers DNA sequencing of all coding exons, as well as MLPA
analysis for the detection of whole-exon or whole-gene duplications within the MEN1 gene. These
analyses detect up to 90% of pathogenic variants in individuals with familial MEN1 and 65% of pathogenic
variants in individuals with no family history.

Prenatal diagnosis is available when a variant has been identified in the family.

Prior to testing, we strongly urge all patients to have genetic counseling to review
their risk of cancer, to discuss possible findings from screening, and to discuss the relevance of these
findings to the management of their health care. Documentation of cancer reported in the family history is
advised.

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MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 (MEN2)
SYNDROME

GENE: RET (ret proto-oncogene)
CHROMOSOMAL LOCATION: 10q11.2
MODE OF INHERITANCE: autosomal dominant

The three subtypes of Multiple endocrine neoplasia type 2 (MEN2) are MEN2A, MEN2B, and
familial medullary thyroid carcinoma (FMTC). All three subtypes are associated with a high risk for developing
medullary thyroid carcinoma (MTC). Individuals with MEN2A typically present in early adulthood and are also at
risk for pheochromocytoma and parathyroid adenoma or hyperplasia. Individuals with MEN2B are also at risk for
pheochromocytoma and can have additional features including mucosal neuromas of the lips and tongue,
ganglioneuromatosis of the gastrointestinal tract, enlarged lips, and a Marfanoid body habitus. MEN2B typically
presents in early childhood. Individuals with FMTC typically present in middle age. Our laboratory offers DNA
sequencing of all coding exons, as well as MLPA analysis for the detection of whole-exon or whole-gene deletions
within the MEN2 gene. These analyses detect greater than 98% of pathogenic variants in MEN2
subtypes MEN2A and MEN2B, and 95% of pathogenic variants in the FMTC MEN2 subtype.

Prenatal diagnosis is available when a variant has been identified in the family.

Prior to testing, we strongly urge all patients to have genetic counseling to review
their risk of cancer, to discuss possible findings from screening, and to discuss the relevance of these
findings to the management of their health care. Documentation of cancer reported in the family history is
advised.

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MYELOPROLIFERATIVE DISEASE

GENES: JAK2 (janus kinase 2)
CALR (calreticulin 3)
MPL (myeloproliferative leukemia virus oncogene)
CHROMOSOMAL LOCATION: 9p24 (JAK2); 19p13.3-p13.2 (CALR);
p34 (MPL)
REGIONS ANALYZED: JAK2 V617F common exon 12 mutation, reflex JAK2 exon 12 sequencing; reflex CALR exon 9
sequencing; reflex MPL exons 1-12 sequencing
MODE OF INHERITANCE: somatic

Variants in the JAK2, MPL, and CALR genes were found in
patients with myeloproliferative disorders. Approximately 50 to 60% of patients with essential thrombocythemia
or primary myelofibrosis carry a variant in the JAK2 gene, and an additional 5 to 10% have activating
variants in the MPL gene. Patients with essential thrombocythemia or primary myelofibrosis that was not
associated with a JAK2 or MPL variant carried a somatic variant in exon 9 of the CALR
gene that is likely pathogenic.

Our laboratory offers DNA testing for the JAK2 V617F exon 12 mutation, DNA
sequencing of exon 12 in the JAK2 gene, DNA sequencing of exon 9 in the CALR gene and DNA
sequencing of exons 1-12 in the MPL gene.

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MYH-ASSOCIATED POLYPOSIS (MAP)

GENE: MUTYH (mutY (E. coli) homolog)
CHROMOSOMAL LOCATION: 1p34.3-32.1
MODE OF INHERITANCE: autosomal recessive

Individuals with MYH-Associated Polyposis (MAP) have a wide range of numbers of colon
polyps, some having less severe polyposis (as in attenuated FAP) and some appearing more like FAP with hundreds
of polyps. Due to the autosomal recessive pattern of inheritance, patients with MAP often have no family history
of colon cancer or polyps. Our laboratory offers DNA sequencing of all coding exons (exons 1-16) as well as MLPA
analysis of select exons for the detection of whole-exon or whole-gene deletions or duplications within the
MUTYH gene.

Prior to testing, we strongly urge all patients to have genetic counseling to review
their risk of colon cancer, to discuss possible findings from screening, and to discuss the relevance of these
findings to the management of their health care. Documentation of cancer reported in the family history is
advised.

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NEMALINE MYOPATHY

GENE: NEB (nebulin)
CHROMOSOMAL LOCATION: 2q22
MUTATIONS ANALYZED: c.9619-2
CARRIER FREQUENCY: 1:168 (Ashkenazi Jewish)
MODE OF INHERITANCE: autosomal recessive

Nemaline myopathy is characterized by muscle weakness (myopathy) throughout the body, with the most severe symptoms
affecting the face, neck, and limbs. Symptoms include feeding and swallowing difficulties, foot deformities,
abnormal curvature of the spine (scoliosis), joint deformities, and in severe cases, breathing difficulties. The
most common type of nemaline myopathy is the congenital type, characterized by muscle weakness and feeding problems
beginning in infancy. People with the childhood-onset type usually develop muscle weakness in adolescence while the
adult-onset type usually develop muscle weakness between ages 20 and 50.

This assay may be ordered alone or as part of the Ashkenazi Jewish panel.

Prenatal testing is available when a mutation is known in the family.

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NEUREXIN 1 (NRXN1)

GENE: NRXN1
CHROMOSOMAL LOCATION: 2p16.3
MODE OF INHERITANCE: autosomal dominant and autosomal recessive

Gene variants in Neurexin 1 may occur in indivdiuals with Pitt Hopkins-like syndrome.
Manifestations include a wide mouth with protruding tongue and drooling, pulmonic stenosis, hyperventilation, a
broad-based gait, severe intellectual disability and scoliosis. Patients with autism or schizophrenia may also
have deletions or other pathogenic variants in this gene. Our laboratory offers sequencing and MLPA of the
entire coding region of the NRXN1 gene.

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NEUROFIBROMATOSIS 1

GENE: NF1 (neurofibromin)
CHROMOSOMAL LOCATION: 17q11.2
MODE OF INHERITANCE: autosomal dominant

Neurofibromatosis 1 (NF1) is characterized by multiple café au lait macules, axillary
and inguinal freckling, neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50%
of individuals with Neurofibromatosis 1. Our laboratory offers DNA sequencing of all coding exons (exons 1-58)
as well as MLPA analysis of select exons for the detection of whole-exon or whole-gene deletions or duplications
within NF1. These analyses detect approximately 90-95% of pathogenic variants in individuals with a
clinical diagnosis of Neurofibromatosis 1.

Sequencing of the NF1 gene is now available using Next Generation Sequencing (NGS) which has the benefits
of including mosaicism detection and targeted enrichment of known intronic mutations.

Prenatal diagnosis is available when a variant has been identified in a family.

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NEUROFIBROMATOSIS TYPE 1-LIKE
SYNDROME (NFLS)

GENE: SPRED1 (sprouty-related, EVH1 domain containing 1)
CHROMOSOMAL LOCATION: 15q14
MODE OF INHERITANCE: autosomal dominant

SPRED1 gene variants have recently been described in multiple patients with a
Neurofibromatosis type 1-like syndrome. The phenotype associated with NFLS consists of multiple café-au-lait
macules, axillary freckling, and macrocephaly. Some patients also have learning disabilities. Of patients
evaluated for NF1 without an identifiable NF1 pathogenic variant, 3-25% have an identifiable
SPRED1 pathogenic variant. Additionally, SPRED1 exonic or whole gene deletions have been seen
in approximately 10% of patients evaluated for NF1 without an identifiable NF1 pathogenic variant.

Analysis of the SPRED1 gene should be considered in patients with no
detectable NF1 variant.

Our laboratory offers DNA sequencing and MLPA of all coding exons (1-7) of the SPRED1
gene.

Prenatal testing is available when a variant is known in the family.

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NEUROFIBROMATOSIS 2

GENE: NF2 (merlin)
CHROMOSOMAL LOCATION: 22q12.2
MODE OF INHERITANCE: autosomal dominant

Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas.
Posterior subcapsular lens cataracts are also common features. Our laboratory offers sequencing of all coding
exons (exons 1-17) as well as MLPA analysis for the detection of whole-exon or whole-gene deletions or
duplications within the NF2 gene. These analyses detect approximately 90% of pathogenic variants in
individuals with a clinical diagnosis of Neurofibromatosis 2.

Prenatal diagnosis is available when a variant has been identified in a family.

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NEUROLIGIN (X-LINKED INTELLECTUAL
DISABILITY/AUTISM/ASPERGER SYNDROME)

GENES: NGLN3 and NGLN4
CHROMOSOMAL LOCATION: Xq13 and Xp22
MODE OF INHERITANCE: X-linked recessive

Pathogenic variants in either of these two X-linked genes have been described in
Autism/PDD/Asperger syndrome and non-specific intellectual disability in males.

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NIEMANN PICK DISEASE, TYPE A

GENE: SMPD1 (acid sphingomyelinase (ASM)/sphingomyelin
phosphodiesterase-1)
CHROMOSOMAL LOCATION: 11p15.4-p15.1
MUTATIONS ANALYZED: R496L, L302P, and fsP330
CARRIER FREQUENCY: 1 in 90 (Ashkenazi Jewish)
MODE OF INHERITANCE: autosomal recessive

Niemann-Pick disease (type A, NPD) is the most common and most severe subtype of NPD.
Patients with NPDA typically have less than 5% of normal acid sphingomyelinase levels, which leads to severe
neurological disease in infancy and early childhood. Three mutations in the SMPD1 gene account for
approximately 94% of all cases of NPDA. This assay may be ordered alone or as part of the Ashkenazi Jewish
panel.

Prenatal testing is available when a mutation is known in the family.

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NOONAN SYNDROME

GENES: PTPN11 (tyrosine-protein phosphatase non-receptor type
11); SOS1 (son of sevenless homolog 1); SOS2 (son of sevenless homolog 2); RAF1 (RAF proto-oncogene
serine/threonine-protein kinase); KRAS (GTPase KRas); NRAS (neuroblastoma RAS viral oncogene homolog); SHOC2
(soc-2 suppressor of clear homolog); BRAF (B-Raf proto-oncogene serine/threonine-protein kinase); CBL (Cbl
proto-oncogene, E3 ubiquitin protein ligase); RIT1 (Ras-like without CAAX 1); LZTR1 (leucine-zipper-like
transcription regulator 1)

CHROMOSOMAL LOCATION: 12q24.1 (PTPN11); 3p25 (RAF1); 2p22-p21 (SOS1); 12p12.1 (KRAS);
1p13.2 (NRAS); 10q25 (SHOC2); 7q34 (BRAF); 11q23.3 (CBL); 1q22 (RIT1); 14q21.3(SOS2); 22q11.21 (LZTR1)

MODE OF INHERITANCE: autosomal dominant

Noonan syndrome is characterized by short stature, distinct facial features, congenital
heart disease, and developmental delay/ intellectual disability. Noonan syndrome is genetically heterogeneous.
Our laboratory offers DNA sequencing of all coding exons of the PTPN11, RAF1, SOS1,
KRAS, NRAS, BRAF, CBL, SOS2, RIT1, and LZTR1
genes, as well as single pathogenic variant analysis (S2G) within the SHOC2 gene. Missense pathogenic
variants in the PTPN11 gene have been detected in approximately 50% of individuals with a clinical
diagnosis of Noonan syndrome. Pathogenic variants in the RAF1 and SOS1 genes have been
observed in 3-17% and 10-13% of patients, respectively. Pathogenic variants in the KRAS and
NRAS genes have been observed in <5% of patients. The S2G SHOC2 pathogenic variant has been
observed in 4-5% of patients with Noonan syndrome, particularly with loose anagen hair. Recently, pathogenic
variants in the SOS2 and LZTR1 genes were observed in 3% of patients (Yamamoto et al. (2015),
J Med Genet 52(6):413-21); in the BRAF gene in <2% of patients (Sarkozy et al. (2009), Hum Mutat 30(4):
695–702); and in the CBL gene in <1% of patients (Martinelli et al. (2010) Am J Hum Genet 87(2): 250–257).
Testing in Noonan syndrome is offered as comprehensive, simultaneous Noonan testing of all 11 Noonan genes (most
time effective, with a significantly shorter turn-around-time) or specific testing of any of these genes can be
ordered. Once a variant in the proband is identified, variant-specific testing in relatives and prenatal
diagnosis is available.

Other indications for Noonan syndrome testing:
For an increased nuchal translucency or cystic hygroma detected on fetal ultrasound our laboratory offers
sequencing of PTPN11, RAF1, SOS1, KRAS, NRAS, BRAF,
CBL, SOS2, RIT1, LZTR1, as well as S2G SHOC2 pathogenic variant
analysis for fetuses.

NOONAN SYNDROME
Complete panel includes sequence analysis of PTPN11, SOS1, KRAS, NRAS,
RAF1, BRAF, CBL, SOS2, RIT1, LZTR1, and SHOC2
pathogenic variant analysis.

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OPITZ G/BBB SYNDROME (X-LINKED)

GENE: MID1 (midline-1)
CHROMOSOMAL LOCATION: Xp22
MODE OF INHERITANCE: X-linked

X-linked Opitz G/BBB syndrome is a multiple congenital anomaly disorder characterized
by characteristic facial anomalies (ocular hypertelorism, prominent forehead, widow’s peak, anteverted nares),
cleft lip and/or palate, genitourinary abnormalities, and developmental delay/intellectual disability. Female
carriers typically only manifest ocular hypertelorism. Our laboratory offers DNA sequencing of all coding exons
(exons 4-12) as well as MLPA analysis for the detection of whole-exon or whole-gene deletions or duplications
within MID1. MID1 is the only gene known to be associated with X-linked Opitz G/BBB syndrome.
This analysis detects up to 45% of pathogenic variants in males with clinically diagnosed Opitz G/BBB syndrome.

This assay may be ordered alone or as part of the X-linked Intellectual Disability
(XLID) panel.

Prenatal testing is available when a variant is known in the family.

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OSTEOGENESIS IMPERFECTA TYPE I, II, III,
IV

GENES: COL1A1 (collagen, type I, alpha 1); COL1A2 (collagen, type I,
alpha 2)
CHROMOSOMAL LOCATION: 17q21.33 (COL1A1), 7q22.1 (COL1A2)
MODE OF INHERITANCE: Autosomal dominant

Osteogenesis imperfecta (OI) is characterized by fractures that occur without or with
minimal trauma, dentinogenesis imperfecta (causing discolored teeth that are prone to loss and breakage), short
stature, and adult-onset hearing loss. The clinical features of OI are quite variable depending on the type:

OI type I: Classic non-deforming OI with blue sclerae
OI type II: Perinatally lethal OI
OI type III: Progressively deforming OI
OI type IV: Common variable OI with normal sclerae

Osteogenesis imperfecta is inherited in an autosomal dominant fashion, with 60% of
types I and IV and almost 100% of types II and III caused by de novo
mutations. Molecular genetic testing of COL1A1 and
COL1A2 detects mutations in approximately 90% of individuals with
OI type I, II, III, or IV. Our laboratory offers DNA sequencing and MLPA analysis of all coding exons within the
COL1A1 and COL1A2
genes.

Testing of these genes may be ordered alone, or as part of the CONNECT2 connective
tissue disorders panel.

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PARAGANGLIOMA-PHEOCHROMOCYTOMA
SYNDROMES

GENES: SDHB (succinate dehydrogenase complex, subunit B) – PGL4; SDHC
(succinate dehydrogenase complex, subunit C) – PGL3; SDHD (succinate dehydrogenase complex, subunit D) – PGL1
CHROMOSOMAL LOCATION: 1p36.1-p35, (SDHB), 1q23.3 (SDHC),11q23 (SDHD)
MODE OF INHERITANCE: autosomal dominant; autosomal dominant with maternal imprinting associated with SDHD
mutations

Paragangliomas, or glomus tumors, are typically slow-growing, highly vascular
neoplasms. Extra-adrenal parasympathetic paragangliomas are located predominantly in the head and neck area,
whereas extra-adrenal sympathetic paragangliomas are typically located in the thorax, abdomen, and pelvis.
Pheochromocytomas are paragangliomas that are confined to the adrenal medulla. Hereditary
paraganglioma-pheochromocytoma (PGL/PCC) syndromes should be considered in all individuals with paragangliomas
and/or pheochromocytomas. These syndromes demonstrate autosomal-dominant inheritance with high, but age-related
penetrance. Interestingly, mutations within the SDHD gene demonstrate a parent of origin effect and
cause disease almost exclusively when they are paternal in origin.

Our laboratory offers DNA sequencing and MLPA analysis of all coding exons within the
SDHB, SDHC, and SDHD genes.

Prenatal diagnosis is available when a variant has been identified in the family.

Approximately 70% of familial cases of head and neck paraganglioma are believed to be
caused by germline pathogenic variants in either SDHB, SDHC, or SDHD. Greater than
90% of hereditary cases of paraganglioma are caused by pathogenic variants or deletions of the SDHB,
SDHC, or SDHD genes. Up to 30% of cases of hereditary cases of pheochromocytoma are caused by
pathogenic variants or deletions of the SDHB, SDHC, or SDHD genes. (Milosevic et al
2010). In addition, pathogenic variants in SDHB and SDHD have been associated with a Cowden
syndrome/Cowden syndrome-like phenotype (Ni et al., American Journal of Human Genetics, 2008).

Timely detection of tumors in those predicted to be affected affords the affected
individual the opportunity to avoid the potential morbidity associated with surgical removal, and mortality that
may accompany local and distant metastases.

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PATERNITY DNA ANALYSIS

We offer DNA analysis testing to determine paternity. This test requires a blood sample
from the potential father(s) and the child(ren). A blood sample from the mother is optional. Fetuses can be
tested by routine fetal sampling procedures (i.e., chorionic villus sampling or amniocentesis), or from cord
blood at the time of birth. The accuracy of paternity DNA analysis is 100% if the potential father is excluded
as the biological father of the child. If the potential father is included as the biological father of the child
the accuracy is greater than 99.9%. This is the required certainty for a court of law. Interested individuals in
the Boston area may call for an appointment to have their blood samples drawn at the Center for Human Genetics,
Inc. Please note that we will require photo identification from adults and photographs will be taken of minors
without photo identification. In addition, cheek swabs are available for young children and babies in lieu of a
blood sample. The accuracy remains the same. Our laboratory can also accept samples drawn at outside
institutions. Please call prior to drawing samples so that we can send you the appropriate legal forms to
complete and send with the samples. Results can be expected in 4-6 weeks. The cost of testing is generally not
covered by any insurance company and must be paid in full the time the samples are submitted. Cash, credit card,
certified check, or money order are acceptable forms of payment.

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PELIZAEUS-MERZBACHER DISEASE/ SPASTIC
PARAPLEGIA 2

GENE: PLP1 (myelin proteolipid protein 1)
CHROMOSOMAL LOCATION: Xq22
MODE OF INHERITANCE: X-linked

Pelizaeus-Merzbacher disease is a neurodegenerative disorder that affects primarily the
white matter of the central nervous system (CNS). The condition typically presents in infancy or early childhood
and is characterized by nystagmus, impaired motor development, ataxia, choreoathetotic movements, dysarthria,
and progressive spasticity. Spastic paraplegia 2 often presents with spastic paraparesis with or without CNS
involvement. Our laboratory offers MLPA analysis of all coding exons for the detection of whole-exon or
whole-gene deletions or duplications within the PLP1 gene. Duplication of PLP1 is the most
frequent pathogenic variant found in approximately 50%-75% of PMD patients, and deletions have been reported in
less than 2% of patients. Additionally, our laboratory offers DNA sequence analysis of all coding exons of the
PLP1 gene. Point pathogenic variants in PLP1 are present in approximately 15%-25% of patients.

These assays are performed concurrently, unless specifically requested to be performed
in a sequential manner.

This assay may be ordered alone or as part of the X-linked Intellectual Disability
(XLID) panel.

Prenatal testing is available when a variant is known in the family.

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PENDRED SYNDROME

GENE: SLC26A4 (solute carrier family 26, member 4) / Pendrin
CHROMOSOMAL LOCATION: 7q31
INHERITANCE: autosomal recessive

Pendred syndrome is one of the most common syndromic forms of deafness. It is an
autosomal recessive disorder associated with developmental abnormalities of the cochlea (Mondini dysplasia),
sensorineural hearing loss, and diffuse thyroid enlargement (goiter). Our laboratory offers testing for the
common mutations (L236P, IVS 8+1, E384G, T416P, and FS400) as well as full sequencing of the SLC26A4
gene. Pendred mutations. Analysis of the 5 common mutations can detect up to 60% of all reported mutations in
the SLC26A4 gene known to cause Pendred syndrome. Mutations in this gene also cause non-syndromic
deafness mapping to 7q31 (DFNB4) as well as enlarged vestibular aqueduct syndrome (EVA)/Mondini dysplasia.
Prenatal diagnosis is available when a variant has been identified in a family.

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PHENYLKETONURIA (PKU)

GENE: PAH (phenylalanine hydroxylase)
CHROMOSOMAL LOCATION: 12q32.2
MODE OF INHERITANCE: autosomal recessive

Phenylketonuria (PKU) is caused by a deficiency in phenyalanine hydroxylase which
results in an intolerance to the dietary intake of the essential amino acid phenylalanine. Without dietary
restriction of phenylalanine, most children with PKU develop profound and irreversible intellectual disability.
Our laboratory offers DNA sequencing of all coding exons (exons 1-13) as well as MLPA analysis for the detection
of whole-exon or whole-gene deletions or duplications within the PAH gene. Together, these analyses are
thought to detect approximately 99% of pathogenic variants in PAH.

Prenatal testing is available when a variant is known in the family.

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PITT-HOPKINS SYNDROME

GENE: TCF4 (transcription factor 4)
CHROMOSOMAL LOCATION: 18q21.1
MODE OF INHERITANCE: autosomal dominant, typically de novo

Pitt Hopkins syndrome (PHS) is characterized by severe psychomotor delay, intellectual
disability including absent speech, and intermittent hyperventiliation episodes. The characteristic facial
gestalt of PHS includes microcephaly, coarse facies, broad nasal bridge, wide mouth, fleshly lips, and
cup-shaped ears. Because of its phenotypic and behavioral overlap (patients with PHS often display a happy
disposition and stereotypic hand movements), PHS is an important differential diagnosis of Angelman and Rett
syndromes.

Our laboratory offers DNA sequencing of all coding exons (exons 2-19) as well as MLPA
analysis for the detection of whole-exon or whole-gene deletions or- duplications within the TCF4 gene.

Prenatal diagnosis is available when a variant has been identified in a family.

Our laboratory offers a comprehensive Angelman / Angelman-like Syndrome panel which
includes:

• • Angelman methylation studies

• • UBE3A sequence analysis

• • SLC9A6 sequence analysis

• • TCF4 analysis

• ZEB2 analysis

Direct testing of any of these genes can be ordered.

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PITT HOPKINS-LIKE SYNDROME

GENE: CNTNAP2 (contactin – associated protein – like 2)
CHROMOSOMAL LOCATION: 7q35-36
MODE OF INHERITANCE: autosomal recessive

Heterozygous, homozygous, and compound heterozygous CNTNAP2 pathogenic
variants have been reported in individuals with a range of clinical presentations, including severe intellectual
disabilities, autism spectrum disorders, autosomal recessive Pitt-Hopkins-like syndrome, and cortical
dysplasia-focal epilepsy (CDFE) syndrome.

Our laboratory offers DNA sequencing of all 24 exons of the CNTNAP2 gene.

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PRADER-WILLI SYNDROME

GENE: SNRPN
CHROMOSOMAL LOCATION: 15q11
INCIDENCE: 1 in 25,000 births
MODE OF INHERITANCE: deletion; uniparental disomy; imprinting defects; some autosomal dominant rearrangements

Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding
difficulties in early infancy, followed by excessive eating and gradual development of morbid obesity (unless
externally controlled) in later infancy and childhood. All patients have some degree of cognitive impairment.
Hypogonadism, short stature, and characteristic behaviors are also common. PWS is caused by a deletion or
disruption of the paternal SNRPN gene region. Our methylation-sensitive MLPA detects deletions of the
paternal chromosome 15 and uniparental disomy of maternal chromosome 15 or an imprinting center defect.
Approximately 98% of PWS cases are detectable using this assay. This direct DNA analysis for PWS is now
recommended for the confirmation of a diagnosis in a patient with or without a family history of the condition.
Karyotyping parents of an affected child and methylation studies of a fetus are available for prenatal
diagnosis. Further studies, such as uniparental disomy studies (which require parental blood samples), are
available and may be recommended following a positive test result.

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PROTHROMBIN

GENE: F2 (coagulation factor II)
CHROMOSOMAL LOCATION: 11p11-q12
INCIDENCE: 1-2% of the Caucasian population
MODE OF INHERITANCE: autosomal dominant

Prothrombin is the precursor of thrombin (the activated form of factor II) in the
clotting cascade. A mutation in the gene for prothrombin causes an elevation of the level of functional
prothrombin in plasma, which is associated with an increased risk of thrombosis. Persons who are at risk to
carry the prothrombin mutation are those with a family history of early onset stroke, deep vein thrombosis,
thromboembolism, pregnancy associated with thrombosis/embolism, hyperhomocystinemia, and multiple miscarriages.
Individuals with the mutation are at increased risk of thrombosis in the setting of oral contraceptive use,
trauma, and surgery. Direct DNA analysis of the Factor V (see above) and prothrombin mutations are now
recommended for at-risk patients because of the importance of therapy and antithrombotic prophylaxis.

This test is also available as part of the thrombophilia panel, which includes testing
for Factor V Leiden and MTHFR.

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PRSS1-RELATED HEREDITARY
PANCREATITIS

GENE: PRSS1 (protease serine 1, cationic trypsinogen)
CHROMOSOMAL LOCATION: 7q35
MODE OF INHERITANCE: autosomal dominant

Chronic pancreatitis (CP) is a persistent inflammation of the pancreas. Hereditary
pancreatitis (HP) is a form of chronic pancreatitis with the presence of a positive family history (three or
more affected members involving at least two generations) that is inherited in an autosomal dominant fashion
with incomplete penetrance and variable expressivity. Idiopathic pancreatitis (IP) is when neither the
precipitating factors nor a positive family history is known.

PRSS1 is considered a highly penetrant gene associated with HP. An estimated
75 to 80% of hereditary pancreatitis (HP) and 10% of idiopathic pancreatitis are due to PRSS1 gene
gain-of-function pathogenic variants. Recently, duplication and triplication of the PRSS1 gene has been
observed in some patients with HP. PRSS1 missense variants stimulate activation of trypsinogen to
trypsin or block degradation of active trypsin, whereas SPINK1 alterations reduce inhibitor levels and
thus compromise trypsin inhibition. It has been recommended (Rosendahl, et al. Nat Genet. 2008, 40:78-82) that
individuals presenting with 1) recurrent unexplained attacks of acute pancreatitis or unexplained CP and a
positive family history, 2) unexplained CP without a positive family history after exclusion of other causes, or
3) unexplained pancreatitis episode in children undergo SPINK1 and PRSS1 molecular testing.

Our laboratory offers DNA sequencing of all coding exons, as well as MLPA analysis for
the detection of whole-exon or whole-gene duplications within the PRSS1 gene.

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X-LINKED INTELLECTUAL DISABILITY/ AUTISM
SPECTRUM DISORDER

GENE: PTCHD1 (patched domain containing 1)
CHROMOSOMAL LOCATION: Xp22.11
MODE OF INHERITANCE: X-linked

Pathogenic variants in the PTCHD1 gene have been found in patients with autism
spectrum disorder and in patients with intellectual disability. Although hypotonia is seen in some patients,
there are no consistent dysmorphic, metabolic or neuromuscular features in addition to the intellectual
disability and/or autism spectrum disorder.

Our laboratory offers DNA sequencing and MLPA analysis for the detection of whole-exon
or whole-gene deletions and duplications of all three coding exons of the PTCHD1 gene.

Prenatal testing is available when a variant is known in the family.

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PTEN-HAMARTOMA TUMOR SYNDROME
(Cowden, Bannayan-Riley-Ruvalcaba, Proteus/Proteus-Like; Autism with macrocephaly)

GENE: PTEN (phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and
dual-specificity protein phosphatase)
CHROMOSOMAL LOCATION: 10q23.3
MODE OF INHERITANCE: autosomal dominant

The PTEN-hamartoma tumor syndrome (PHTS) includes Cowden syndrome,
Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome. This group of disorders shares
significant clinical overlap, most notably predisposition to hamartomatous polyposis of the GI tract. Cowden
syndrome is characterized by increased risk for both benign and malignant tumors of the breast, thyroid, and
endometrium. Affected individuals have macrocephaly and almost all will develop mucocutaneous lesions including
trichilemmomas, papillomatous papules, and acral and plantar keratoses. Bannayan-Riley-Ruvalcaba syndrome is a
congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, and enlargement and spotty
pigmentation of the glans penis. Proteus and Proteus-like syndromes are congenital disorders with hamartomatous
overgrowth of any tissue. Our laboratory offers DNA sequencing of the promoter region, all coding exons, as well
as MLPA analysis of the PTEN gene. Sequence analysis of the PTEN gene detects pathogenic
variants in approximately 80% of individuals with a clinical diagnosis of Cowden syndrome, 60% of individuals
with a clinical diagnosis of Bannayan-Riley-Ruvalcaba syndrome, 50% of individuals with a clinical diagnosis of
Proteus-like syndrome, and 20% individuals with a clinical diagnosis of Proteus syndrome. Deletions in
PTEN are thought to account for approximately 10% of individuals with a clinical diagnosis of
Bannayan-Riley-Ruvalcaba syndrome. Sequencing of the promoter region of PTEN detects pathogenic
variants that alter gene function in approximately 10% of individuals with a clinical diagnosis of Cowden
syndrome who do not have an identifiable pathogenic variant in the PTEN coding region.

Prenatal testing is available when a variant has been identified in a family.

Other phenotypes caused by pathogenic variants in PTEN:

• • Adult onset Lhermitte-Duclos disease

• Patients with autism spectrum disorder and macrocephaly

Autism spectrum disorders are a group of neurodevelopmental disorders, in which
patients show deficits in social interaction, impaired communication, repetitive behavior and restricted
interests and activities. It is reported that 25-30% of patients with autism spectrum disorders have a head
circumference greater than the 98th percentile. It is reported that 20% of individuals with autism spectrum
disorders and macrocephaly have PTEN pathogenic variants.

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RETT SYNDROME

GENE: MECP2 (methyl-CpG-binding protein 2)
CHROMOSOMAL LOCATION: Xp11
MODE OF INHERITANCE: X-linked

Rett syndrome is a progressive neurological disorder in which individuals exhibit
reduced muscle tone, autistic-like behavior, microcephaly, wringing and flapping hand movements, loss of
purposeful use of the hands, diminished ability to express feelings, avoidance of eye contact, a lag in brain
and head growth, gait abnormalities, and seizures. Symptoms typically occur between ages 6 and 18 months. Our
laboratory offers DNA sequencing of the MECP2 gene for the identification of pathogenic variants in
this gene. Sequencing of exons 1-4 will detect approximately 80% of patients with Rett syndrome. MLPA analysis
will detect an additional 10-12% of individuals with classic Rett syndrome who have a large deletion or
duplication, not detectable by routine sequencing analysis.

Prenatal diagnosis is available when the MECP2 variant has been identified in
a family.

Other phenotypes caused by pathogenic variants in MECP2:

• • Males with X-linked intellectual disability and
    spasticity (OMIM# 300055)

• • Males with X-linked intellectual disability, Lubs
    type (OMIM# 300260)

• • Males with neonatal-onset encephalopathy (OMIM#
    300673)

• • Females with Angelman-like phenotype

• • Males with PPM-X (psychosis, pyramidal signs, and
    macroorchidism)

• • Preserved-speech variant Rett syndrome

• “Forme-fruste” Rett syndrome

Our laboratory offers a comprehensive Rett syndrome (classic, atypical, and congenital
variants) panel which includes:

• • MECP2 analysis

• • CDKL5/STK9 analysis

• • FOXG1 analysis

• TCF4
  analysis

(See other individual entries for other CPT codes.)

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RETT SYNDROME – ATYPICAL

GENE: CDKL5/STK9 (cyclin-dependent kinase-like 5; serine/threonine
protein kinase 9)
CHROMOSOMAL LOCATION: Xp22
MODE OF INHERITANCE: X-linked

Pathogenic variants in the CDKL5 gene (also known as STK9) have been
associated with an atypical variant of Rett syndrome, with severe early-onset seizures or infantile spasms, loss
of communication and motor skills, and severe intellectual disability. The CDKL5/STK9-associated
phenotype may be severe, with early-onset encephalopathy, infantile spasms, severe global developmental delay,
and profound intellectual impairment seen in female and male patients. At the mild end of the spectrum are
patients with mild intellectual disability with autistic features. Many of these clinical features meet the
criteria for the early-onset variant of Rett syndrome.
Our laboratory offers DNA sequencing of all coding exons (exons 2-21) as well as MLPA analysis for the detection
of whole-exon or whole-gene deletions or duplications within the CDKL5/STK9 gene.

Prenatal diagnosis is available when a variant has been identified in a family.

Patients who previously tested negative for comprehensive variant analysis in the
MECP2 gene are candidates for CDKL5/STK9 sequence analysis.

Other phenotypes caused by pathogenic variants in CDKL5/STK9:

• Females with West syndrome (infantile spasms,
  hypsarrhythmia, and intellectual disability

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RETT SYNDROME – CONGENITAL VARIANT
FORM

GENE: FOXG1 (forkhead box G1)
CHROMOSOMAL LOCATION: 14q13
MODE OF INHERITANCE: autosomal dominant, typically de novo

The FOXG1 gene has been implicated as the molecular cause of the congenital
variant of Rett syndrome. Patients with FOXG1 pathogenic variants often demonstrate normal birth
parameters, followed by hypotonia and extreme irritability in the neonatal period. Deceleration of head growth
often becomes apparent in the first months of life resulting in severe microcephaly by 4 to 5 months of age.
Similar to classic Rett syndrome, these patients demonstrate stereotypic hand movements (hand washing and hand
mouthing), and have limited/absent language development. In contrast to classic Rett syndrome, patients often
show poor/absent eye contact, and frequent tongue thrusting behaviors. It has been recommended that
FOXG1 analysis be performed in female and male patients demonstrating features of the congenital
variant of Rett syndrome.

Our laboratory offers DNA sequencing of the coding exon, as well as MLPA analysis for
the detection of whole-exon or whole-gene deletions or- duplications within the FOXG1 gene.

Prenatal diagnosis is available when a variant has been identified in a family.

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SCN1A

GENE: SCN1A (sodium channel, voltage-gated, type I, alpha subunit)
CHROMOSOMAL LOCATION: 2q24
MODE OF INHERITANCE: autosomal dominant

SCN1A is part of a cluster of sodium channel genes. Variants in this gene are
associated with a range of phenotypes that include generalized epilepsy with febrile seizures, early infantile
epileptic encephalopathy, Dravet syndrome and intractable childhood epilepsy, severe myoclonic epilepsy of
infancy, Lennox-Gastaut syndrome, infantile spasms, vaccine-related encephalopathy, and seizures. An additional
phenotype includes familial hemiplegic migraine. Our laboratory offers sequencing and MLPA of the entire coding
region of the SCN1A gene.

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SICKLE CELL ANEMIA

GENE: hemoglobin beta (HBB)
CHROMOSOMAL LOCATION: 11p
CARRIER FREQUENCY: 1 in 10 African-Americans
MODE OF INHERITANCE: autosomal recessive

Sickle cell disease is characterized by variable degrees of hemolysis and intermittent
episodes of vascular occlusion resulting in tissue ischemia and acute and chronic organ dysfunction. Resulting
complications include anemia, jaundice, predisposition to aplastic crisis, sepsis, cholelithiasis, and delayed
growth. The change in the beta globin gene that causes sickle-cell anemia has been well described. Our assay
differentiates beta globin A, S, and C. Thus we are able to detect sickle-cell anemia, SC disease, “sickle
trait” (carriers of the S allele), and “C trait” (carriers of the C allele). Direct DNA analysis of the beta
globin gene is available for prenatal diagnosis when both parents are known or suspected carriers.

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SLC16A2-SPECIFIC THYROID HORMONE CELL
TRANSPORTER DEFICIENCY (Allan-Herndon-Dudley, Triiodothyronine resistance, X-linked ID with
hypotonia)

GENE: MCT8/ SLC16A2 (solute carrier family 16 (monocarboxylic acid
transporters), member 2
CHROMOSOMAL LOCATION: Xq13.2
MODE OF INHERITANCE: X-linked

Pathogenic variants in the MCT8/SLC16A2 gene are associated with intellectual
disability, impaired speech, and congenital hypotonia with eventual spasticity. The MCT8/SLC16A2 gene
is important for the neuronal uptake of triiodothyronine (T3) in its function as a specific and active
transporter of thyroid hormones across the cell membrane. Therefore, pathogenic variants in
MCT8/SLC16A2 typically cause elevated serum levels of free T3, and low-normal serum levels of free T4.
Levels of TSH are typically within the normal range.

Our laboratory offers DNA sequencing of all coding exons (1-6) of the
MCT8/SLC16A2 gene.

This assay may be ordered alone or as part of the X-linked Intellectual Disability
(XLID) panel.

Prenatal testing is available when a variant is known in the family.

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SMITH-LEMLI-OPITZ SYNDROME (SLO)

GENE: DHCR7 (7-dehydrocholesterol reductase)
CHROMOSOMAL LOCATION: 11q12-q13
CARRIER FREQUENCY: 1 in 100 individuals
MODE OF INHERITANCE: autosomal recessive

Smith-Lemli-Opitz (SLO) is characterized by failure to thrive, microcephaly,
developmental delay, ptosis, hypospadias, dysmorphic features, syndactyly, low total cholesterol and elevated
7-dehydrocholesterol. Sequence analysis of 7 exons of the SLO gene, which detects up to 90% of all known
pathogenic variants, is offered at our laboratory.

Prenatal diagnosis is available when the DHCR7 variants have been identified
in the family.

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SNP MICROARRAY (6.0)

6.0 DNA-SNP MICROARRAY
IMPORTANT NEW DNA TEST FOR UNEXPLAINED INTELLECTUAL DISABILITY, AUTISM, AND/OR CONGENITAL MALFORMATIONS

This new test enables the analysis of 1.8 million copy number probes/single nucleotide
bases (termed SNPs – single nucleotide polymorphisms) distributed throughout the human genome, facilitating the
detection of microdeletions or microduplications of 50 or more SNPs (termed CNV – copy number variants).

SCOPE: This test will detect:

1. 1. All microdeletions/microduplications throughout
      the genome including many known syndromes.

1. All numerical chromosome abnormalities including
   trisomies, monosomies, unbalanced translocations, mosaicism and supernumerary (marker) chromosomes.

BENEFIT: This new advance is valuable and important and WILL:

1. 1. Enable recognition of significant and often
      unexpected microdeletions/duplications throughout the genome (Y- chromosome excluded). The coverage
      is MORE EXTENSIVE AND LESS EXPENSIVE THAN ANY OTHER EQUALLY COMPREHENSIVE AVAILABLE MICROARRAY.

1. 1. Recognize microdeletions/duplications not
      determinable by gene sequencing and be valuable in detecting these abnormalities in about 10% of
      those with autism.

1. 1. Add a 10-20% detection rate to the diagnosis of
      unexplained intellectual disability/congenital malformations after negative results on karyotyping.

1. 1. Not only target specific disorders, as in other
      microarrays, but cover the genome including subtelomeric regions, supplemented by an additional
      assay at no extra cost.

1. 1. Be valuable in those individuals with
      intellectual disability and/or anomalies who have previously been determined to have “balanced
      chromosome rearrangements”.

1. 1. No longer require separate assays for routine
      comparative genomic hybridization or subtelomeric chromosome analysis.

1. Recognize uniparental disomy for any autosomal chromosome
   pair (when specifically ordered).

LIMITATIONS:

1. 1. The samples are analyzed at a resolution of 50 Kb
      for the known microdeletion/duplication syndromes and subtelomeric regions. The remaining genome is
      analyzed at a resolution of 200 Kb (deletions less than 200 Kb and duplications less than 500 Kb are
      not reported).

1. 1. Balanced structural rearrangements (balanced
      translocations, inversions) will not be detectable.

1. Single gene mutations usually determinable by gene
   sequencing will not be detectable.

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SOTOS SYNDROME

GENE: NSD1 (histone-lysine N-methyltransferase, H3 lysine-36 and H4
lysine-20 specific)
CHROMOSOMAL LOCATION: 5q35
MODE OF INHERITANCE: autosomal dominant

Sotos syndrome is an overgrowth condition characterized by typical facial features
(long narrow face, prominent narrow jaw, frontal bossing, malar flushing), and developmental delay/intellectual
disability. Among individuals with classic Sotos syndrome, approximately 50% of individuals of Japanese ancestry
and 10% of individuals of non-Japanese ancestry have a 5q35 microdeletion that encompasses the NSD1
gene. Our laboratory offers MLPA analysis of the NSD1 gene which is designed to detect whole-exon or
whole-gene deletions. Among individuals with classic Sotos syndrome, approximately 30-90% of individuals of
non-Japanese ancestry and 10-12% of individuals of Japanese ancestry have an NSD1 sequence pathogenic
variant. Our laboratory offers sequencing of all coding exons (exons 2-23) of the NSD1 gene. These
assays are performed concurrently, unless specifically requested to be performed in a sequential manner.

Prenatal diagnosis is available when a variant has been identified in a family.

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SPINAL MUSCULAR ATROPHY (SMA)

GENE: SMN1 (survival of motor neuron 1, telomeric)
CHROMOSOMAL LOCATION: 5q13.2
MODE OF INHERITANCE: autosomal recessive

Spinal muscular atrophy (SMA) is a genetic disorder which causes degeneration and loss
of the anterior horn cells (motor neurons) of the brain stem and spinal cord, resulting in progressive muscle
weakness and loss of motor control. Common complications include failure to thrive, scoliosis, joint
contractures, respiratory issues, and sleeping difficulties. Severity and age of onset are variable. Children
with SMA type I (Werdnig-Hoffman) have severe weakness before six months of age, do not achieve any motor
milestones, have trouble eating and breathing, and have a significantly decreased life expectancy. Individuals
with SMA type II (Dubowitz) have onset of muscle weakness between 6 and 18 months, and gain only the ability to
sit independently (typically lost by adolescence). Individuals with SMA type III (Kugelberg-Welander) have onset
of muscle weakness after one year of age and are typically able to walk independently until their 30s-40s,
though they may have frequent falls or trouble with stairs. Individuals with SMA type IV have onset of muscle
weakness in adulthood (usually 20s – 30s) with decreased ambulation.

Our laboratory offers MLPA analysis of exons 7 and 8 of the SMN1 gene. This
analysis detects 95 to 98% of individuals with a clinical diagnosis of SMA. This analysis can not detect the 2
to 5% of individuals with a duplication (2 copies) on one allele and a deletion (0 copies) on the other, as the
duplication “masks” the deletion.

Prenatal diagnosis is available for families in which there is an affected child or
both parents are known carriers. Carrier testing is also available. There is a 1/40 to 1/60 carrier frequency
for SMA, depending on parental ethnicity.

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SPINK1-RELATED HEREDITARY
PANCREATITIS

GENE: SPINK1 (serine protease inhibitor Kazal-type 1, pancreatic
secretory trypsin inhibitor)
CHROMOSOMAL LOCATION: 5q32
MODE OF INHERITANCE: autosomal recessive, multifactorial

Chronic pancreatitis (CP) is a persistent inflammation of the pancreas. Hereditary
pancreatitis (HP) is a form of chronic pancreatitis with the presence of a positive family history (three or
more affected members involving at least two generations) that is inherited in an autosomal dominant fashion
with incomplete penetrance and variable expressivity. Idiopathic pancreatitis (IP) is when neither the
precipitating factors nor a positive family history is known. Compared to PRSS1 pathogenic variants,
SPINK1 pathogenic variants are thought to have lower penetrance, and thus considered an intermediate
penetrance gene. An estimated 15% of individuals with IP have loss-of-function SPINK1 pathogenic
variants. Entire gene deletions have also been described in some patients with IP. PRSS1 missense
variants stimulate activation of trypsinogen to trypsin or block degradation of active trypsin, whereas
SPINK1 alterations reduce inhibitor levels and thus compromise trypsin inhibition. It has been
recommended (Rosendahl J et al. Nat Genet. 2008;40:78-82) that individuals presenting with 1) recurrent
unexplained attacks of acute pancreatitis or unexplained CP and a positive family history, 2) unexplained CP
without a positive family history after exclusion of other causes, and 3) unexplained pancreatitis episode in
children have SPINK1 and PRSS1 molecular testing.

Our laboratory offers DNA sequencing of all coding exons, as well as MLPA analysis for
the detection of whole-exon or whole-gene duplications within the SPINK1 gene.

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STICKLER SYNDROME TYPE I

GENE: COL2A1 (collagen α1(II) chain)
CHROMOSOMAL LOCATION: 12q13.11-q13.2
MODE OF INHERITANCE: autosomal dominant

Stickler syndrome is an autosomal dominant connective tissue disorder that includes
ophthalmologic (myopia, cataract, and retinal detachment), craniofacial (Pierre Robin sequence: micrognathia,
glossoptosis, cleft palate, midface hypoplasia), audiologic (hearing loss), and joint abnormalities (early
arthritis, mild spondlyepiphyseal dysplasia). Pathogenic variants in three genes, COL2A1,
COL11A1, and COL11A2, have been associated with the Stickler syndrome, termed Stickler
syndrome type I, II, and III respectively. Individuals with pathogenic variants in the COL2A1 gene
typically have type I “membranous” congenital vitreous anomaly and milder hearing loss.

Our laboratory offers DNA sequencing of all 54 coding exons in COL2A1, as well
as MLPA analysis of select exons for the detection of whole-exon or whole-gene deletions or duplications. These
analyses detect 80-90% of pathogenic variants in individuals with a clinical diagnosis of Stickler syndrome.

Prenatal testing is available when a variant has been identified in a family.

Other diseases caused by pathogenic variants in COL2A1:

• • Achondrogenesis Type II (OMIM# 200610)

• • Kniest Dysplasia (OMIM# 156550)

• • Spondyloepiphyseal Dysplasia, Congenita (OMIM#
    183900)

• • Spondyloepimetaphyseal Dysplasia Strudwick type
    (OMIM# 184250)

• • Spondyloperipheral Dysplasia (OMIM# 271700)

• • Early-onset arthropathy

• • Avascular necrosis of the femoral head, primary
    (ANFH) (OMIM# 08805)

• Autosomal dominant rhegmatogenous retinal detachment
  (ARDD)

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STICKLER SYNDROME TYPE II

GENE: COL11A1 (collagen, type XI, alpha 1)
CHROMOSOMAL LOCATION: 1p21
MODE OF INHERITANCE: autosomal dominant

Stickler syndrome is an autosomal dominant connective tissue disorder that includes
ophthalmologic (myopia, cataract, and retinal detachment), craniofacial (Pierre Robin sequence: micrognathia,
glossoptosis, cleft palate, midface hypoplasia), audiologic (hearing loss), and joint abnormalities (early
arthritis, mild spondlyepiphyseal dysplasia). Pathogenic variants in three genes, COL2A1,
COL11A1, and COL11A2, have been associated with Stickler syndrome, termed Stickler syndrome
type I, II, and III respectively. Individuals with pathogenic variants in the COL11A1 gene typically
have type II “beaded” congenital vitreous anomaly and significant hearing loss.

Our laboratory offers DNA sequencing of all coding exons in the COL11A1 gene,
as well as MLPA analysis for the detection of whole-exon or whole-gene deletions or duplications. These analyses
detect 10-20% of pathogenic variants in individuals with a clinical diagnosis of Stickler syndrome.

Prenatal testing is available when a variant has been identified in a family.

Other diseases caused by pathogenic variants in COL11A1:

• Marshall syndrome (OMIM# 154780)

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STICKLER SYNDROME TYPE III

GENE: COL11A2 (collagen, type XI, alpha 2)
CHROMOSOMAL LOCATION: 6p21.3
MODE OF INHERITANCE: autosomal dominant

Stickler syndrome is an autosomal dominant connective tissue disorder that includes
ophthalmologic (myopia, cataract, and retinal detachment), craniofacial (Pierre Robin sequence: micrognathia,
glossoptosis, cleft palate, midface hypoplasia), audiologic (hearing loss), and joint abnormalities (early
arthritis, mild spondlyepiphyseal dysplasia). Pathogenic variants in three genes, COL2A1,
COL11A1, and COL11A2, have been associated with Stickler syndrome, termed Stickler syndrome
type I, II, and III respectively. Individuals with pathogenic variants in the COL11A2 gene typically
have the craniofacial abnormalities, joint manifestations, and hearing loss typical of Stickler syndrome, but do
not have significant ocular findings.

Our laboratory offers DNA sequencing for all coding exons in the COL11A2 gene.

Prenatal testing is available when a variant has been identified in a family.

Other diseases caused by pathogenic variants in COL11A2:

• • Autosomal recessive otospondylometaepiphyseal
    dysplasia (OMIM# 215150)

• Weissenbach-Zweymuller syndrome (OMIM#277610)

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TAY-SACHS DISEASE

GENE: HEXA (beta-hexosaminidase alpha chain)
CHROMOSOMAL LOCATION: 15q23-q24
MUTATIONS ANALYZED: 1277insTATC, IVS12+1(G->C), IVS 7+1(G->A)/G269S, and 7.6kb del
CARRIER FREQUENCY: 1 in 30 (Ashkenazi Jewish or French Canadian); 1 in 256 (Other) **Carrier frequency in Cajun
and Old Order Amish populations may be higher
MODE OF INHERITANCE: autosomal recessive

Classic Tay-Sachs disease (TSD) is a progressive neurodegenerative condition with
typical onset between 3-6 months of age. There are also juvenile and adult forms of TSD. In almost all cases of
Tay-Sachs disease there is a mutation in the HEXA gene, which can be detected using a panel of 5
mutations. Specifically, 98% of mutations in the Ashkenazi Jewish population are detected by this screen; 80-85%
of mutations in the French Canadian population; and 38% of mutations in individuals who are neither of Ashkenazi
Jewish nor French Canadian ancestry. The American College of Obstetrics & Gynecology (ACOG) recommends
carrier screening for couples in which at least one person is of Ashkenazi Jewish or French Canadian ancestry.
Direct DNA analysis is also available for patients who have signs or symptoms suggestive of this disorder.

Prenatal diagnosis is available when mutations in the family are known.

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THORACIC AORTIC
ANEURYSMS/DISSECTIONS

GENES: ACTA2 (actin, alpha 2, smooth muscle, aorta); FBN1 (fibrillin
1); MYH11 (myosin-11); MYLK (myosin light chain kinase); NTM (neurotrimin); PRKG1 (protein kinase,
cGMP-dependent, type I); SMAD3 (mothers against decapentaplegic, drosophila,
homolog of, 3); TGFβ2 (transforming growth factor, beta – 2); TGFβR1 (transforming growth factor-beta receptor,
type I); TGFβR2 (transforming growth factor-beta receptor, type II)
CHROMOSOMAL LOCATION: 10q23.3 (ACTA2); 15q21.1 (FBN1); 16p13.13-p13.12 (MYH11); 3q21.1 (MYLK); 11q25 (NTM);
10q11.2 (PRKG1); 15q22.33 (SMAD3); 1q41 (TGFβ2); 9q33-34 (TGFβR1); 3p22 (TGFβR2)
MODE OF INHERITANCE: autosomal dominant

Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited
in isolation or in association with genetic syndromes, such as Marfan syndrome and Loeys-Dietz syndrome. When
TAAD occurs in the absence of syndromic features, the disease is referred to as familial TAAD and is inherited
in an autosomal dominant manner with decreased penetrance and variable expression. Familial TAAD exhibits
significant clinical and genetic heterogeneity. Pathogenic variants in the ACTA2 gene are thought to
account for approximately 10-14% of familial TAAD. Approximately 4% of individuals with TAAD have pathogenic
variants in TGFβR2, and approximately 1-2% have pathogenic variants in either TGFβR1 or
MYH11. Pathogenic variants have been identified in TGFβ2 that result in a phenotype similar to
those patients with pathogenic variants in TGFβR1 or TGFβR2 (common features include tall
stature, pectus deformity, club foot, aortic root aneurysm, and hernias). Pathogenic variants in MYH11
have been described in individuals with TAAD with patent ductus arteriosus (PDA). Pathogenic variants within the
SMAD3 gene have been reported in patients with a syndromic form of aortic aneurysms and dissections
with early onset osteoarthritis and are thought to account for approximately 2% of familial TAAD. Pathogenic
variants have been described in MYLK and PRKG1 in families with familial aortic aneurysms that
lead to acute aortic dissections. In addition, FBN1 pathogenic variants have also been reported in
individuals with TAAD. There is considerable phenotypic overlap with pathogenic variants in FBN1,
TGFβR1 or TGFβR2, SMAD3, and TGFβ2. Pathogenic variants in the NTM
gene have been identified in rare families with intracranial and thoracic aortic aneurysms.

Our laboratory offers DNA sequencing of all coding exons of the ACTA2,
FBN1, MYH11, MYLK, NTM, PRKG1, SMAD3, TGFβ2,
TGFβR1, and TGFβR2 genes, as well as MLPA analysis for the detection of whole-exon or
whole-gene deletions or duplications in the FBN1, MYH11, SMAD3, TGFβ2,
TGFβR1, and TGFβR2 genes.