The relationship between GM2A and Tay Sachs disease, AB variant, a rare, autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 1, 2022. GM2A encodes the GM2 activator protein (GM2AP), a small glycolipid transport protein which is essential for the lysosomal breakdown of GM2-gangliosides, sialic acid-containing glycosphingolipids which are components of the plasma membrane, by hexosaminidase A. A deficiency of the GM2AP results in accumulation of GM2-ganglioside and related glycolipids in the lysosomes of neurons, resulting symptoms indistinguishable from the classical Tay-Sachs phenotype. This includes developmental regression, seizures, exaggerated startle response, and presence of a cherry red spot in the retina (Toro et al, 2020, PMID 20301397).
Biallelic variants in GM2A were first reported in patients with Tay Sachs disease, AB variant, in 1991 (Schröder et al, PMID: 1915858). Since then, fifteen families with biallelic variants in GM2A and features of Tay Sachs disease, AB variant, have been reported (İnci et al, 2021, PMID: 33819415, Table1). The mechanism of disease is loss of function.
In this curation, data on 10 unique variants (3 nonsense, 1 frameshift, 1 canonical splice site, 3 missense, 2 in frame indels) from 8 probands from 7 publications were collected (Schröder et al, 1991, PMID: 1915858; Schröder et al, 1993, PMID: 8244332; Schepers et al, 1996, PMID: 8900233; Chen et al, 1999, PMID: 10364519; Sheth et al, 2016, PMID: 27402091; Martins et al, 2017, PMID: 28417072; İnci et al, 2021, PMID: 33819415). Further information is available in the literature but the maximum score for genetic evidence (12 points) has been reached.
Experimental evidence supporting this gene-disease relationship includes the biochemical function of the GM2 activator protein, which is consistent with the biochemical and clinical findings in patients (Smiljanic-Georgijev et al, 1997, PMID: 9187239; Mahuran 1998, PMID: 9714704; Mahuran 1999, PMID: 10571007). The gene product of GM2A is known to interact with the gene product of HEXA, a gene definitively associated with Tay Sachs disease. Lastly, the phenotype of a Gm2a knock out mouse recapitulates the GM2 ganlioside accumulation and some clinical features of Tay Sachs disease (Liu et al, 1997, PMID 9223328).
In summary, GM2A is definitively associated with Tay Sachs disease, AB variant. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the Lysosomal Diseases GCEP on August 12, 2022 (SOP v9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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