Tay-Sachs Disease (HEXA) Sequencing and Deletion/Duplication

Last Literature Review: November 2021 Last Update:

Use to confirm pathogenic and pseudodeficiency HEXA gene variants in individuals with abnormal levels of HEX A enzyme, a suspected diagnosis of HEXA deficiency, and/or suspected carrier status.

Individuals of French Canadian descent may benefit from targeted Tay-Sachs screening. If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate. Refer to the Laboratory Test Directory for additional information and test options.

Tay-Sachs disease is a genetic disorder caused by a 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 those of Ashkenazi Jewish or French Canadian descent. Molecular testing can identify pathogenic and pseudodeficiency HEXA gene variant(s) in individuals with abnormal HEX A activity.  

Disease Overview


Varies by ethnicity:

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



HEXA (NM_000520)


Over 130 HEXA variants have been identified. The majority are null alleles that result in no HEX A enzymatic activity. The 7.6kb deletion is the only recurring large deletion.

Commonly Detected Variant(s) by Ethnicity
Ethnicity Variant(s)

Ashkenazi Jewish

  • 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

French Canadian

7.6kb deletion is the most common pathogenic variant

General population

~36% of individuals with enzyme level in the carrier range have pseudodeficiency alleles (eg, c.739C>T [p.R247W] and c.745C>T [p.R249W])


Autosomal recessive

Test Interpretation


This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for the detection of large (single exon-level or larger) deletions and duplications.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and to confirm variant calls in certain situations.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Clinical Sensitivity


Analytic Sensitivity

Variant Class Analytic Sensitivity (PPA) Estimatea (%)
and 95% Credibility Region (%)
Analytic Specificity (NPA) (%)


>99 (96.9-99.4)


Deletions 1-10 bpb

93.8 (84.3-98.2)


Insertions 1-10 bpb

94.8 (86.8-98.5)


Exon-levelc Deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [single exon]


Exon-levelc Duplications

83.3 (56.4-96.4) [3 exons or larger]


aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. These values do not apply to testing performed by MLPA.

bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; MLPA, multiplex ligation-dependent probe amplification; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants


Result Variant(s) Detected Interpretation


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


No pathogenic HEXA gene variant detected

Pseudodeficiency alleles will be reported but are considered clinically insignificant

Decreases the likelihood the individual is affected with, or a carrier of, HEX A deficiency


Sequence variant(s) of uncertain clinical significance identified

Unknown if variant(s) are disease-causing or benign


  • A negative result does not exclude a diagnosis of Tay-Sachs disease.
  • Diagnostic errors can occur due to rare sequence variants.
  • Interpretation of this test may be impacted if this patient has had an allogeneic stem cell transplantation.
  • This assay detects the 7.6kb deletion at a reduced sensitivity. Therefore, individuals of French Canadian descent may benefit from targeted screening; refer to the Laboratory Test Directory for available test options.
  • The following will not be evaluated:
    • Variants outside the coding regions of intron-exon boundaries of the HEXA gene
    • Regulatory region and deep intronic variants
    • Breakpoints of large deletions/duplications
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by MPS
    • Large duplications less than 3 exons in size
    • Noncoding transcripts.
    • Low-level somatic variants
    • Certain other variants, due to technical limitations in the presence of pseudogenes or repetitive/homologous regions