Download Test Information Sheet HEXA Gene Analysis in Tay

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Test Information Sheet
HEXA Gene Analysis in Tay-Sachs Disease
Mendelian Inheritance in Man Numbers: 272800 –Tay-Sachs Disease; 606869- HEXA gene
Clinical features:
Tay-Sachs disease (TSD) is a lysosomal storage disorder with symptoms ranging from an acute infantile form
(classic TSD) to subacute juvenile and adult onset forms with later onset and slower disease progression. Infants
with classic TSD generally appear normal at birth. At 3-6 months of age motor weakness, myoclonic jerks and an
exaggerated startle reaction are usually the presenting features followed by developmental retardation and
regression, paralysis, dementia and blindness with death by the second or third year of life. A cherry-red macula is
a typical fundoscopic finding and, histologic examination reveals the lysosomal accumulation of GM2 gangliosides
represented as distended, ballooned neurons in the central nervous system. The juvenile and adult forms have
more variable neurologic findings, including progressive dystonia, spinocerebellar degeneration, motor neuron
disease, and in some individuals with the adult onset form, a bipolar form of psychosis.1 The juvenile and adult
onset forms differ from each other primarily by the impact of the disease on intelligence, which is minimal through
much of the course of the adult form.2 The carrier frequency in Ashkenazi Jews is approximately 1 in 30, while the
carrier in Sephardic Jews and non-Jews is approximately 1 in 250 to 1 in 300.1 Other groups that are relatively
genetically isolated have also been found to have carrier frequencies similar to or higher than that observed in
Ashkenazi Jews including French Canadians from eastern Quebec, Cajuns from Louisiana and the Old Order
Amish in Pennsylvania.1
Inheritance pattern: Autosomal Recessive
Genetics and biochemical features:
TSD is caused by mutations in the HEXA gene encoding the α-subunit of the β-hexosaminidase A (Hex A) enzyme.
Hex A binds the GM2 activator/ GM2 ganglioside complex and hydrolyzes GM2 to GM3. Patients with TSD have
absent to near-absent Hex A enzyme activity in serum, white blood cells or other tissues resulting in the intralysosomal accumulation of GM2 ganglioside. The HEXA gene is located on chromosome 15q23-q24 and has 14
exons.
Reasons for referral:
1. Confirmation of biochemical diagnosis especially in those with borderline enzyme activity
2. Full sequence analysis for non-Jewish partners of individuals who are known to be a mutation carrier
3. Carrier testing
4. Genetic counseling
5. Prenatal diagnosis in at risk pregnancies
Test method:
Mutation analysis of the HEXA gene is performed on genomic DNA from the submitted specimen using bidirectional sequence analysis of coding exons and corresponding intron/exon boundaries. If full sequencing
identifies a mutation on only one allele of the HEXA gene, and if clinically indicated, reflex deletion/duplication
testing (ExonArrayDx) will be performed at no additional charge to evaluate for a deletion/duplication of one or
more exons of this gene. Mutations found in the first person of a family to be tested are confirmed by repeat
analysis using sequencing, restriction fragment analysis or another appropriate method.
Test sensitivity:
In two studies of non-Ashkenazi Jewish patients with TSD, sequence analysis of the HEXA gene identified
mutations on 78/78 alleles.3,4 In another study of non-Jewish TSD unaffected carriers, sequence analysis of the
HEXA gene identified mutations in 30 of 33 (91%) of cases.5
Information Sheet on Tay-Sachs Disease
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GeneDx 05/2013
Mutation spectrum:
More than 100 mutations have been identified in the HEXA gene including missense, nonsense, splicing, small
deletions/insertions and a large 7.6-kb deletion that is common in the non-Jewish French Canadian population from
eastern Quebec.6, 7, 11 In the Ashkenazi Jewish population, three mutations (c.1278insTATC, IVS12+1 G>C and
p.G269S) account for approximately 98% of all mutant alleles.8 The c.1278insTATC and IVS12+1 G>C
mutations (90-95% of alleles in Ashkenazi Jews) are associated with infantile onset TSD, while the p.G269S
mutation (3% of alleles in Ashkenazi Jews) is associated with the adult-onset form.1 An IVS9+1 G>A splice site
mutation has been identified on approximately 17% of alleles from non-Jewish Caucasians with TSD and is
associated with infantile onset.9 Approximately 35% of non-Jewish individuals identified through carrier screening
programs are carriers of one of two pseudodeficiency alleles (p.R247W and p.R249W) which is associated with
low or absent Hex A activity with synthetic substrate, but not associated with a disease phenotype.1, 10 The
p.R178H mutation, found predominately in the Portuguese, is associated with the juvenile phenotype.1 Other
genotype/phenotype correlations have also been reported.1, 10
Specimen Requirements and Shipping/Handling:
 Blood: A single tube with 1-5 mL whole blood in EDTA (1-2mL for infants). Ship overnight at ambient
temperature, using a cool pack in hot weather. Specimens may be refrigerated for one week prior to shipping.
 Buccal Brushes: CANNOT be accepted for this test.
 Prenatal Diagnosis: For prenatal testing for a known mutation in the HEXA gene, please refer to the specimen
requirements table on our website at: http://www.genedx.com/test-catalog/prenatal/. Ship specimen overnight
at ambient temperature, using a cool pack in hot weather.
Required Forms:
Sample Submission (Requisition) Form – complete all pages
Payment Options Form or Institutional Billing Instructions
For test codes, prices, CPT codes, and turn-around-times, please refer to the “Tay-Sachs Disease” page on
our website: www.genedx.com
References: 1. Kaback, M. (Updated [May 19, 2006]) Hexosaminidase A Deficiency In: GeneReviews at Genetests: Medical Genetics
Information Resource (database online). Copyright, University of Washington, Seattle. 1997- 2007. Available at
http://www.genetests.org. 2. Maegawa et al., (2006) Pediatrics 118:e1550-e1562. 3. Giraud et al., (2010) Biochem Biophys Res
Commun 392:599-602. 4. Montalvo et al., (2005) Hum Mutat 26:282. 5. Park et al., (2010) Pediatr Res 67:217-20. 6. Myerowitz,
R. And Hogikyan, N. (1986) Science 232:1646-1648. 7. Hechtman et al., (1992) Hum Genet 90:402-406. 8. Triggs-Raine et al.,
(1990) N Engl J Med 323:6-12. 9. Akerman et al., (1992) Hum Mutat 1:303-309. 10. Cao et al., (1997) J Biol Chem 272:1497514982. 11. Braekeleer et al., (1992) Hum Genet 89:83-87.
Information Sheet on Tay-Sachs Disease
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GeneDx 05/2013