HEXA rs28941771: Tay-Sachs Disease Carrier Status
The genetic variant rs28941771 is a single nucleotide polymorphism located in the HEXA gene on chromosome 15. It represents a pathogenic missense mutation cataloged in ClinVar and OMIM as conferring carrier status for Tay-Sachs disease (a form of GM2 gangliosidosis). Inherited in an autosomal recessive manner, individuals carrying a single altered allele are asymptomatic carriers, whereas inheriting two defective HEXA copies can cause severe lysosomal dysfunction.
What each genotype means
Increased risk of GM2-gangliosidosis
This genotype is associated with the presence of a pathogenic variant in the HEXA gene, which is linked to late-onset GM2-gangliosidosis. Individuals with this genotype should consult with a genetic counselor or medical professional to understand the clinical implications and potential for disease expression.
This specific genotype is rare in the general population.
Carrier of Tay-Sachs mutation
This genotype indicates you are a carrier of a pathogenic variant in the HEXA gene. Carriers are typically unaffected, but they may have a risk of passing the variant to their children, which is a factor to consider for family planning.
Carrier status for HEXA variants is notably enriched in French Canadian and Cajun populations compared to the general population.
Typical HEXA genotype
This genotype represents the common, non-pathogenic state for this specific variant location. It does not indicate carrier status for the pathogenic HEXA variant associated with Tay-Sachs disease at this position.
This is the most common genotype observed in the general population.
Genomic Context and Variant Identity
The rs28941771 variant is an alterable locus mapped to chromosome 15q23 inside the human HEXA gene. In genomic databases such as dbSNP and ClinVar, this variant represents a single base change that leads to a missense amino acid substitution in the encoded enzyme. Because different sequencing technologies and chip-based arrays may read DNA strands in the forward or reverse orientation, rs28941771 is often cataloged with alleles reflecting complementary nucleotides (such as A/G or T/C depending on genomic strand alignment). ClinVar flags this alteration as pathogenic, specifically classifying it in the context of GM2-gangliosidosis, including juvenile or late-onset phenotypes when inherited alongside another pathogenic variant in trans. Understanding the exact reference and alternate alleles is essential for clinical interpretation, as carrier screening tests must accurately determine which parent strand was surveyed.
Biological Function of the HEXA Gene
The HEXA gene encodes the alpha subunit of beta-hexosaminidase A, an essential hydrolytic enzyme located in the lysosomes of cells. Together with the beta subunit (encoded by HEXB) and the GM2 activator protein, beta-hexosaminidase A breaks down complex glycosphingolipids, specifically GM2 gangliosides, which are abundant in the membranes of neuronal tissue. Normal cellular function requires sufficient active beta-hexosaminidase A to continuously recycle these lipids. When missense mutations like rs28941771 compromise protein folding, stability, or catalytic active sites, the cellular degradation pathway fails. Over time, the inability to hydrolyze GM2 gangliosides leads to excessive, toxic lipid accumulation inside neuronal lysosomes, ultimately triggering progressive neurodegeneration and loss of motor and cognitive functions characteristic of Tay-Sachs disease spectrum disorders.
Evidence Strength and Clinical Phenotype
Tay-Sachs disease is an autosomal recessive disorder, meaning an individual must inherit pathogenic variations on both HEXA alleles to develop symptoms. Evidence supporting the pathogenicity of rs28941771 is curated across ClinVar, OMIM (entry 606869), and peer-reviewed literature. However, the cataloged evidence strength for this specific missense alteration is characterized as limited relative to the highly recurrent, well-characterized 4-base-pair insertions or canonical splice-site changes typical of classic infantile forms. The phenotypic expression of this missense alteration can vary depending on whether the second inherited allele is a complete null mutation or carries partial residual activity. Heterozygous individuals carrying only one copy of rs28941771 remain clinically unaffected, without signs of neurodegeneration, though they face reproductive risks if their partner is also a carrier.
Population Distribution and Founder Effects
In the global general population, pathogenic variants in the HEXA gene are extraordinarily rare, with overall carrier frequencies often estimated around 1 in 250 to 1 in 300. However, specific founder mutations have reached much higher frequencies in historically isolated or bottlenecked populations. Beyond the widely known enrichment among individuals of Ashkenazi Jewish heritage, distinct HEXA disease alleles are significantly enriched in French Canadian communities of Quebec and in the Cajun population of southern Louisiana. Because of these founder effects, targeted preconception carrier screening protocols often evaluate HEXA variants in people tracing ancestry to these regions. In broad datasets such as gnomAD, rs28941771 remains an infrequent finding outside of these specific demographic enclaves.
Navigating Results: What This Information Means for You
Identifying an altered allele at rs28941771 on an educational genetic report is not a personal medical diagnosis of Tay-Sachs disease. Because of the recessive nature of GM2 gangliosidosis, an individual with a single variant allele is simply a carrier and will not experience symptoms. However, carrier status has profound significance for reproductive planning: if both reproductive partners carry a pathogenic HEXA variant, there is a 25% chance in each pregnancy of having an affected child. Direct-to-consumer testing microarrays can produce false positives or fail to identify complex deletions and pseudodeficiency alleles. Anyone receiving a positive carrier signal should consult a certified genetic counselor or medical geneticist for clinical-grade diagnostic sequencing, partner screening, and family planning guidance.
How common is this variant?
The rs28941771 variant is very rare in the broader global population, but it is notably enriched as a founder allele in French Canadian and Cajun populations.
Frequently asked questions
Does having a HEXA rs28941771 variant mean I will get Tay-Sachs disease?
No, having a single variant copy simply means you are a carrier. Tay-Sachs disease is inherited in an autosomal recessive manner, requiring two altered HEXA gene copies to cause symptoms. Carriers produce enough functional beta-hexosaminidase A to remain completely healthy.
Why is this variant linked to French Canadian and Cajun ancestry?
Historical population bottlenecks and founder effects caused certain genetic variants to become more common in these communities compared to the worldwide average. During colonization and subsequent geographic isolation, specific HEXA mutations were passed down through generations at an elevated frequency.
Can consumer DNA tests definitively confirm my carrier status?
Direct-to-consumer arrays often screen only a small subset of known variants and can yield both false positives and false negatives. Furthermore, they frequently miss pseudodeficiency alleles or large structural deletions. A clinical laboratory panel and a consultation with a genetic counselor are recommended for definitive preconception screening.
What is the difference between Tay-Sachs disease and pseudodeficiency?
A pseudodeficiency allele is a harmless genetic change in HEXA that lowers enzyme activity in artificial lab assays but functions fine in the human body. Clinical laboratories must differentiate genuine pathogenic mutations like rs28941771 from pseudodeficiency variants to avoid misdiagnosing healthy individuals.
Sources & further reading
Educational information only, last refreshed 9/8/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Canonical splice junction variant (c.1073+1G>A) causing Tay-Sachs disease.
Pathogenic splice-junction variant (c.1073+1G>A / IVS9+1G>A) causing Tay-Sachs disease when in compound heterozygosity or homozygosity.
Pathogenic splice donor variant (c.1421+1G>C) in HEXA underlying carrier status for autosomal recessive infantile Tay-Sachs disease.
This HEXA variant is associated with Tay-Sachs disease, particularly late-onset forms.
Pathogenic splice junction mutation (c.1421+1G>C) in HEXA leading to Tay-Sachs disease.
Pathogenic HEXA splice donor site mutation (c.1073+1G>A) causing Tay-Sachs disease, common in carrier screening panels for Ashkenazi Jewish and French Canadian ancestry.