Gene Validity Curation

HEXA - Tay-Sachs disease

Gene: HEXA (HGNC:4878)
Classification - 05/27/2020
Disease: Tay-Sachs disease (MONDO_0010100)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: General Gene Curation EP
Evidence Summary: 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.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 9
17
12
Myerowitz R et al. 1988 Dec 15 (PMID:2848800); Paw BH et al. 1990 Jun 5 (PMID:2140574); Myerowitz R et al. 1987 Nov 15 (PMID:2824459); Zampieri S et al. 2012 May 15 (PMID:22441121); Navon R et al. 1989 Mar 17 (PMID:2522679);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0.25
Paw BH et al. 1990 Jun 5 (PMID:2140574);
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.2 1
Navon R et al. 1989 Mar 17 (PMID:2522679);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.2    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
2
2
Li YT et al. 1973 Nov 10 (PMID:4745777);
Protein Interaction 0.5 0 - 2 1 2
Lemieux MJ et al. 2006 Jun 16 (PMID:16698036);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Paw BH et al. 1990 Jun 5 (PMID:2140574);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Torres PA et al. 2010 Dec (PMID:20817517); Yamanaka S et al. 1994 Oct 11 (PMID:7937929);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 2
4
Gray-Edwards HL et al. 2018 Mar (PMID:28922945); Tropak MB et al. 2016 Mar 2 (PMID:26966698);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
05/27/2020
EXPERT CURATION (DATE)
Definitive
05/27/2020
EVIDENCE SUMMARY
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.