HEXA

Chr 15AR

hexosaminidase subunit alpha

Also known as: TSD

NCBI Gene: 3073 ENSG00000213614 UniProt: P06865 OMIM: 606869

This gene encodes the alpha subunit of beta-hexosaminidase A, a lysosomal enzyme that degrades GM2 ganglioside and other molecules containing terminal N-acetyl hexosamines. Biallelic mutations cause autosomal recessive GM2 gangliosidosis, including Tay-Sachs disease, due to GM2 ganglioside accumulation in neurons leading to neurodegeneration. The pathogenic mechanism involves loss of enzymatic function resulting in toxic substrate accumulation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

[Hex A pseudodeficiency]MIM #272800

GM2-gangliosidosis, several formsMIM #272800

Tay-Sachs diseaseMIM #272800

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Tay-Sachs disease · AR · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.97

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — HEXA

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.97LOEUF

pLI 0.000

Z-score 1.68

OE 0.68 (0.49–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.41Z-score

OE missense 1.07 (0.97–1.18)

297 obs / 277.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.68 (0.49–0.97)

0≤0.351.4

Missense OE?1.07 (0.97–1.18)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 22 / 32.3Missense obs/exp: 297 / 277.8Syn Z: 0.32

Background carrier burden — how many people carry a rare variant somewhere in HEXA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 81

713 rare PASS variants

Rare truncating (LoF)

1 in 300

121 rare PASS variants

Rare synonymous (reference)

1 in 230

261 rare PASS variants

Rare missense and truncating variants are carried at similar rates in HEXA; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 320
South Asian	~43k	1 in 54	1 in 1,400
Remaining (unassigned)	~30k	1 in 69	1 in 250
European (Finnish)	~27k	1 in 250	1 in 990
Admixed American	~22k	1 in 77	1 in 1,000
African / African American	~21k	1 in 52	1 in 580
East Asian	~20k	1 in 90	1 in 520
Ashkenazi Jewish	~13k	1 in 560	none seen
Middle Eastern	~2,884	1 in 130	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 14 coding exons well covered in gnomAD exomes; exons 3, 6 marginal. Genomes: all 14.? see exons ↓