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

  • 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
  • If results are negative and patient is of French Canadian descent, consider ordering Tay-Sachs Disease (HEXA), 7 Variants.
Related Tests

Use to confirm common pathogenic and pseudodeficiency HEXA gene variants (including the 7.6kb pathogenic deletion) in individuals of Ashkenazi Jewish or French Canadian descent and/or with abnormal levels of HEX A enzyme

  • Use to test for known familial pathogenic sequencing variant(s)
  • A copy of the relative’s laboratory report documenting the familial variant(s) is REQUIRED.

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

Incidence

Varies by ethnicity:

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

Genetics

Gene

HEXA (NM_000520)

Variants

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])

Inheritance

Autosomal recessive

Test Interpretation

Methodology

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

99%

Analytical Sensitivity

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

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-levelc Deletions

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

62.5 (38.3-82.6) [single exon]

>99.9

Exon-levelc Duplications

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

>99.9

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 analytical 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

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

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

Uncertain

Sequence variant(s) of uncertain clinical significance identified

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

Limitations

  • 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 (Tay-Sachs Disease (HEXA), 7 Variants).
  • 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

References

  1. GeneReviews - HEXA disorders

    Toro C, Shirvan L, Tifft C. HEXA disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2021. [Last update: Oct 2020; Accessed: Aug 2021]