Submission Details

The relationship between HEXA and Tay-Sachs disease, an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 16, 2020. HEXA encodes the alpha subunit of beta-hexosaminidase A (Hex A), a lysosomal enzyme that hydrolyzes the terminal beta-linked N-Acetylgalactosamine (GalNAc) from GM2 ganglioside to produce GM3 ganglioside (gangliosides are the main glycolipids of neuronal cell plasma membranes). Deficiency of Hex A activity results accumulation of GM2 ganglioside and related glycolipids in the lysosomes, particularly in nerve cells. The most severe form, the acute infantile variant, is characterized by progressive weakness, loss of motor skills, decreased attentiveness, and increased startle response with onset between 3-6 months of age followed by progressive neurodegeneration including seizures, blindness, spasticity, eventual total incapacitation, and death, usually before 4 years. The juvenile (subacute), chronic, and adult-onset variants of hexosaminidase A deficiency have later onsets, slower progression, and more variable neurologic findings, including progressive dystonia, spinocerebellar degeneration, motor neuron disease, and, in some individuals with adult-onset disease, a bipolar form of psychosis (from GeneReviews; https://www.ncbi.nlm.nih.gov/books/NBK1218/; see also PMIDs 29152458, 30524313). Variants in HEXA were first reported in humans with Tay-Sachs disease in 1986 (Myerowitz and Hogikyan, PMID 3754980). Since then, over 175 variants have been reported (PMID 29152458). Founder variants associated with acute infantile Tay-Sachs disease in the Ashkenazi Jewish population are p.Tyr427IlefsTer5 (~80% of alleles) and c.1421+1G>C (~15% of alleles).A 7.6 kb deletion is commonly found in French-Canadian patients, and c.1073+1G>A in other patients with acute infantile Tay-Sachs disease. Another variant, p.Gly269Ser, causes adult-onset disease and accounts for up to 5% of alleles in Ashkenazi Jewish and non-Ashkenazi Jewish populations (see GeneReviews - https://www.ncbi.nlm.nih.gov/books/NBK1218/). The mechanism of disease is loss of function Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Ten variants in ten probands from five publications were curated (Myerowitz et al, 1987; PMID 2824459; Myerowitz et al, 1988, PMID 2848800; Navon and Proia, 1989, PMID 2522679; Paw et al, 1999, PMID 2140574; Zampieri et al, 2012, PMID 22441121) and included frameshift, nonsense, large deletion, splice site, and missense variants. One of the probands came from a family in which 3 affected siblings had the same genotype (Navon and Proia, 1989, PMID 2522679). More information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of Hex A, deficiency of which is consistent with the accumulation of GM2 ganglioside in the nerve cells of affected patients (Li et al, 1973, PMID 4745777); the finding that the Hex A alpha subunit (encoded by HEXA) interacts with the beta-subunit of Hex A (encoded by HEXB), and the GM2 r protein (encoded by GM2A) and that variants in these other genes also cause GM2 gangliosidosis (Lemieux et al, 2006, PMID 16698036); studies showing defects in the production and function of Hex A in cultured fibroblasts from affected individuals (Paw et al, 1999, PMID 2140574); the phenotype observed in laboratory-generated and naturally-occurring animal models (Yamanaka et al, 1994, PMID 7937929; Torres et al, 2010, PMID 20817517), and the amelioration and delay of symptoms in animal models treated by gene therapy (Tropak et al, 2016, PMID 26966698; Gray-Edwards et al, 2018, PMID 28922945). More information in available in the literature but the maximum score for experimental evidence (6 points) has been reached. In summary, HEXA is definitively associated with Tay-Sachs disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.