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Tay-Sachs Disease via the HEXA Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
7889 HEXA 81406 81406,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7889HEXA81406 81406,81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Jana Paderova, PhD

Clinical Features and Genetics

Clinical Features

Tay-Sachs disease (TSD), also known as GM2 Gangliosidosis Type 1, is a neurodegenerative lysosomal storage disorder due to deficiency in the enzyme beta-hexosaminidase A. The enzymatic deficiency results in the accumulation of the lipid GM2 ganglioside, the natural substrate for beta-hexosaminidase A, mainly in nerve cells of the brain and retina. Two main variants of TSD are recognized.

Infantile acute TSD is the most severe and most prevalent variant. It is characterized by onset before the age of 6 months, rapid progression and death by 4 years of age, usually from bronchopneumonia. Symptoms at onset include muscle weakness and atrophy, hypotonia, exaggerated startle response, cherry-red spot in the macula, and decline in psychomotor functions. Abnormal eye movements, visual difficulties and seizures of variable types occur later. Symptoms progress rapidly to blindness, deafness, and generalized paralysis, leading eventually to death (Gravel et al. In: Scriver et al. 2001).

Late-onset TSD is clinically heterogeneous in regards to the age of onset of symptoms, clinical features, and progression rate. It is further divided into subacute TSD and chronic TSD. In the subacute TSD, symptoms begin between 2-5 years of age and death occurs in the second decade of life, usually from infections. Symptoms include ataxia, loss of movement coordination, spasticity, dystonia, slow deterioration of speech, gait and posture, cerebellar atrophy, dementia, and loss of vision (Maegawa et al. 2006). In chronic TSD, age of onset varies from childhood to late adulthood and symptoms include seizures, unsteady gait and slow neurological deterioration with cognitive loss and psychosis (Johnson 1981; Navon and Proia 1989).

Genetics

All TSD variants are inherited in an autosomal recessive manner and result from pathogenic variants in the HEXA gene (Myerowitz and Hogikyan 1986). TSD occurs worldwide, with a carrier frequency of 1/250 in the general population. It is however more prevalent in the Ashkenazi Jewish and Quebec French Canadian populations with carrier frequencies of 1/30 and 1/14, respectively (Kaback 2000).

Over 160 pathogenic variants have been reported and include missense, nonsense, splicing, small insertions/deletions and one large deletion. Pathogenic variants occur throughout the HEXA gene and have been reported in patients from various ethnic and geographic backgrounds such as Argentinean (Zampieri et al. 2012), Indian (Mistri et al. 2012), and Spanish (Gort et al. 2012). However, four prevalent variants have been identified. Three of these, c.1274_1277dupTATC (p.Tyr427IlefsStop5), c.1421+1G>C, and c.805G>A, (p.Gly269Ser), account for the majority of pathogenic variants in Ashkenazi Jewish populations. The fourth variant is a 7.6-kb deletion found mainly in the Quebec French Canadian population (Myerowitz and Hogikyan 1986).

Two sequence variants in the HEXA gene (c.739C>T, p.Arg247Trp and c.745C>T, p.Arg249Trp) result in pseudodeficiency of the HEXA enzyme in the presence of the artificial substrate that is used in the enzyme assay. These two variants were identified in ~36% of non-Jewish individuals and ~ 3% of Jewish individuals who were found to have HEXA enzyme activity in the heterozygous carrier range by population based screening. These variants result in normal enzyme activity in-vivo and do not cause disease (Triggs-Raine et al. 1992; Cao et al. 1993; Cao et al. 1997; Kaback and Desnick 2011).

The HEXA gene encodes the alpha-subunit of the beta-hexosaminidase A enzyme, which is involved in the biodegradation of GM2 ganglioside.

Clinical Sensitivity - Sequencing with CNV PG-Select

This test detects pathogenic variants in over 98% of Ashkenazi Jewish individuals with a diagnosis of TaySachs disease (Kaback et al. 1993) and in about 94% of non-Ashkenazi Jewish individuals (Strom et al. 2013).

Pathogenic deletions in the HEXA gene are rare. Only one such deletion has been reported in the Quebec French Canadian population (Myerowitz and Hogikyan 1986).

Testing Strategy

This test provides full coverage of all coding exons of the HEXA gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

This test is indicated for patients with symptoms suggestive of GM2 gangliosidosis, deficient HEXA enzyme activity, and normal HEXB enzyme activity; and family members of patients with pathogenic variants in the HEXA gene. This test is also indicated for asymptomatic individuals who are found to have HEXA enzyme activity in the heterozygous carrier range by population based screening. It allows the distinction between pseudodeficiency alleles and disease-causing alleles. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in HEXA.

Gene

Official Gene Symbol OMIM ID
HEXA 606869
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Tay-Sachs Disease AR 272800

Related Test

Name
Tay-Sachs Disease via the French Canadian Deletion in the HEXA Gene

Citations

  • Cao Z, Natowicz MR, Kaback MM, Lim-Steele JS, Prence EM, Brown D, Chabot T, Triggs-Raine BL. 1993. A second mutation associated with apparent beta hexosaminidase A pseudodeficiency: identification and frequency estimation. Am J Hum Genet 53:1198-1205. PubMed ID: 7902672
  • Cao Z, Petroulakis E, Salo T, Triggs-Raine B. 1997. Benign HEXA mutations, C739T(R247W) and C745T(R249W), cause beta-hexosaminidase A pseudodeficiency by reducing the alpha-subunit protein levels. J Biol Chem 272:14975-14982. PubMed ID: 9169471
  • Gort L, de Olano N, Macías-Vidal J, Coll MA; Spanish GM2 Working Group. 2012. GM2 gangliosidoses in Spain: analysis of the HEXA and HEXB genes in 34 Tay-Sachs and 14 Sandhoff patients. Gene 506:25-30. PubMed ID: 22789865
  • Gravel RA, Kaback MM, Proia RL, Sandhoff K, Suzuki K and Suzuki K. 2001. The GM2 Gangliosidoses.  In: Scriver et al. Eds 8 Vol 3 McGraw-Hill, New York, 3827-3877.
  • Johnson WG. 1981. The clinical spectrum of hexosaminidase deficiency diseases. Neurology. 31:1453-1456. PubMed ID: 7198192
  • Kaback M, Lim-Steele J, Dabholkar D, Brown D, Levy N, Zeiger K. 1993. Tay-Sachs disease--carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network. JAMA 270:2307-2315. PubMed ID: 8230592
  • Kaback MM, Desnick RJ. 2011. Hexosaminidase A Deficiency. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301397
  • Kaback MM. 2000. Population-based genetic screening for reproductive counseling: the Tay-Sachs disease model. Eur J Pediatr 159 Suppl 3:S192-195. PubMed ID: 11216898
  • Maegawa GH, Stockley T, Tropak M, Banwell B, Blaser S, Kok F, Giugliani R, Mahuran D, Clarke JT. 2006. The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. Pediatrics 118:e1550-1562. Review. PubMed ID: 17015493
  • Mistri M, Tamhankar PM, Sheth F, Sanghavi D, Kondurkar P, Patil S, Idicula-Thomas S, Gupta S, Sheth J. 2012.  Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India. PLoS One 7:e39122. PubMed ID: 22723944
  • Myerowitz R and Hogikyan ND. 1986. Different mutations in Ashkenazi Jewish and non-Jewish French Canadians with Tay-Sachs disease. Science 232:1646-1648. PubMed ID: 3754980
  • Navon R and Proia RL. 1989. The mutations in Ashkenazi Jews with adult GM2 gangliosidosis, the adult form of Tay-Sachs disease. Science 243:1471-1474. PubMed ID: 2522679
  • Strom CM, Park NJ, Morgan C, Lobo R, Crossley B, Sharma R, Bonilla-Guerrero R and Denise Salazar D. 2013. Tay-Sachs carrier screening in the genomics age: Gene sequencing versus enzyme analysis in non-Jewish individuals. Open Journal of Genetics 03: 61–66.
  • Triggs-Raine BL, Mules EH, Kaback MM, Lim-Steele JS, Dowling CE, Akerman BR, Natowicz MR, Grebner EE, Navon R, Welch JP, et al. 1992.  A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening. Am J Hum Genet 51:793-801. PubMed ID: 1384323
  • Zampieri S, Montalvo A, Blanco M, Zanin I, Amartino H, Vlahovicek K, Szlago M, Schenone A, Pittis G, Bembi B, Dardis A. 2012. Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation. Gene 499:262-265. PubMed ID: 22441121

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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