Tay-Sachs Disease Testing

Preferred test to evaluate symptomatic patients for Tay-Sachs disease or Sandhoff disease

  • Molecular testing is recommended to confirm disease status and exclude pseudodeficiency

Can identify carriers of Tay-Sachs disease

  • False positive results can be seen in serum/plasma from pregnant individuals, individuals who use oral contraceptives or hormone replacement therapy, or individuals with liver or autoimmune disease
  • Molecular testing is recommended to exclude pseudodeficiency

Can identify carriers of Sandhoff disease

Evaluate symptomatic patients for Tay-Sachs disease or Sandhoff disease

Preferred test to identify carriers of Tay-Sachs disease

  • Use in pregnant individuals, individuals who use oral contraceptives or hormone replacement therapy, individuals with liver or autoimmune disease, or individuals with a previous inconclusive HEX A enzyme test in plasma/serum
  • Molecular testing recommended to exclude pseudodeficiency

Preferred test to identify carriers of Sandhoff disease

Can be used to evaluate symptomatic patients for Tay-Sachs disease or Sandhoff disease

Can identify carriers of Tay-Sachs disease

  • Plasma/serum assayed first; reflexes to leukocytes for inconclusive/abnormal results

Can identify carriers of Sandhoff disease

Tay-Sachs Disease (HEXA) Sequencing and 7.6kb Deletion 2009298
Method: Polymerase Chain Reaction/Sequencing/Gel Electrophoresis

Confirm pathogenic and pseudodeficiency HEXA gene variants in individuals with abnormal levels of HEX A enzyme

Related Tests
Tay-Sachs Disease (HEXA), 7 Variants 0051428
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Confirm common pathogenic and pseudodeficiency HEXA gene variants in individuals of Ashkenazi Jewish or French Canadian descent with abnormal levels of HEX A enzyme

Included in a panel of tests for common disorders/variants for screening individuals of Ashkenazi Jewish descent

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Useful when a known pathogenic familial variant has been identified by sequencing.

Tay-Sachs disease is a genetic disorder that causes deficiency of the hexosaminidase A (HEX A) enzyme. Patients with Sandhoff disease also lack HEX A activity, together with hexosaminidase B (HEX B) activity. Screening for Tay-Sachs carrier status should be performed for individuals from high-risk populations, especially individuals of Ashkenazi Jewish or French Canadian descent. HEX A enzymatic activity is the initial test to suggest a diagnosis in symptomatic individuals or to determine carrier status. Genetic testing can identify causative HEXA gene variant(s) in individuals with abnormal HEX A activity.  

Testing Strategy

  • HEX A enzymatic activity:
    • Initial test to evaluate symptomatic individuals
    • First-tier test to determine carrier status
    • Leukocytes specimen appropriate for individuals who are pregnant, use oral contraceptives, have severe liver or autoimmune disease, or have a previous inconclusive result with different specimen type
    • Plasma or serum specimen appropriate for all other individuals
  • Molecular testing of HEXA gene:
    • Identify pathogenic variant(s) when HEX A enzyme activity is abnormal
    • Distinguish pseudodeficiency alleles from pathogenic variants
    • HEXA common variants panel is recommended for individuals of Ashkenazi Jewish ethnicity
    • Tay-Sachs disease sequencing and deletion is recommended for all other ethnicities

Disease Overview

Incidence

Varies by ethnicity:

  • 1/3,000 in individuals of Ashkenazi Jewish, French Canadian, and Cajun descent 
  • 1/300,000 for the general population 

Diagnostic Issues

  • Affected individuals have absent or extremely low HEX A enzymatic activity
  • Enzymatic testing cannot predict disease severity
  • Milder variant forms of Tay-Sachs disease, such as the B1 variant, may not be identified by enzymatic assay

Screening Issues

Pseudodeficiency alleles: clinically benign variants that have reduced HEX A enzyme activity toward synthetic substrates but have normal activity in vivo

  • Heterozygotes have HEX A activity level in the carrier range
  • Molecular testing is necessary to distinguish pathogenic variants from pseudodeficiency alleles
  • Common pseudodeficiency alleles:
    • c.739C>T (p.R247W)
    • c.745C>T (p.R249W)

Genetics

Gene

HEXA

Inheritance

Autosomal recessive

Variants

  • >130 HEXA variants have been identified
    • Majority are null alleles that result in no HEX A enzymatic activity
    • 7.6kb deletion is the only recurring large deletion
  • Commonly detected variants vary by ethnicity
    • Individuals of Ashkenazi Jewish descent:
      • c.1274_1277dupTATC severe variant accounts for 80% of all pathogenic HEXA variants
      • c.805G>A (p.G269S) variant is typically associated with adult-onset HEX A deficiency
      • ~2% of individuals with enzyme level in the carrier range have pseudodeficiency alleles
    • Individuals of French Canadian descent: 7.6kb deletion is the most common pathogenic variant
    • General population: ~36% of individuals with enzyme level in the carrier range have pseudodeficiency alleles

Test Interpretation

Tay-Sachs Disease (HEXA) Sequencing and 7.6kb Deletion

Sensitivity/Specificity

  • Clinical: 99%
  • Analytical: >99%

Results

Result Variant(s) detected Interpretation

Positive

Heterozygous: one pathogenic HEXA gene variant detected

Individual is at least a carrier of HEX A deficiency

 

Homozygous: more than one pathogenic HEXA gene variants detected

Diagnosis of HEX A deficiency confirmed

Negative

No pathogenic HEXA gene variant detected

Pseudodeficiency alleles will be reported but are considered clinically insignificant

Greatly decreased probability that the individual is affected with, or a carrier of, HEX A deficiency

Inconclusive

Sequence variant(s) of uncertain clinical significance identified

Unknown clinical significance

Limitations

  • Regulatory region and deep intronic variants will not be detected
  • Large deletions/duplications in HEXA other than the 7.6kb deletion will not be detected
  • Diagnostic errors can occur due to rare sequence variations
References 
  1. Kaback M, Desnick R. Hexosaminidase A Deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, eds. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last Update: Aug 2011; Accessed: Jul 2019]
  2. ACOG Committee on Genetics. Committee Opinion No. 690 Summary: Carrier Screening in the Age of Genomic Medicine. Obstet Gynecol. 2017; 129(3): 595-596. PubMed

Last Update: August 2019