ATRX, which encodes a chromatin remodeler, was first reported in relation to X-linked ATR-X-related syndrome in 1995 (Gibbons et al., PMID: 7697714). X-linked alpha thalassaemia intellectual disability (ATR-X) syndrome in males is associated with profound intellectual disability, facial dysmorphism, genital abnormalities, and alpha thalassaemia. Alpha thalassaemia is observed in approximately 75% of affected individuals. Female carriers are typically unaffected, and have skewed X inactivation. Seven variants (2 missense, 2 nonsense, 1 frameshift, 1 canonical splice site, and 1 near splice site) that have been reported in 10 probands in 6 publications (PMIDs: 7697714, 10204841, 11559911, 20500465, 23681356, 24805811) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by two knockout mouse models, and a physical association with MECP2, involved in Rett syndrome (PMIDs: 15668733, 20865721, 21209221, 17296936). In summary, there is definitive evidence to support the relationship between ATRX and ATR-X-related syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 27, 2018. It was recurated on September 29, 2021, and as a result of this re-evaluation, the classification did not change.
ATRX, which encodes a chromatin remodeler, was first reported in relation to X-linked ATR-X-related syndrome in 1995 (Gibbons et al., PMID: 7697714). X-linked alpha thalassaemia intellectual disability (ATR-X) syndrome in males is associated with profound intellectual disability, facial dysmorphism, genital abnormalities, and alpha thalassaemia. Alpha thalassaemia is observed in approximately 75% of affected individuals. Female carriers are typically unaffected, and have skewed X inactivation.
Seven variants (2 missense, 2 nonsense, 1 frameshift, 1 canonical splice site, and 1 near splice site) that have been reported in 10 probands in 6 publications (PMIDs: 7697714, 10204841, 11559911, 20500465, 23681356, 24805811) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by two knockout mouse models, and a physical association with MECP2, involved in Rett syndrome (PMIDs: 15668733, 17296936, 20865721, 21209221).
In summary, there is definitive evidence supporting the relationship between ATRX and ATR-X-related syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 27, 2018. It was recurated on September 29, 2021, and as a result of this re-evaluation, the classification did not change.
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