ANK2 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2012 (Iossifov et al., PMID: 22542183). Individuals with variants in this gene have presented with neurodevelopmental phenotypes including autism spectrum disorder, intellectual disability, seizures, and microcephaly.
Seven de novo protein truncating variants (frameshift and nonsense) that have been reported in 8 probands in 7 publications (PMIDs: 22542183, 25363768, 27479843, 28554332, 30564305, 30755392, 31981491) are included in this curation. More evidence is available in the literature (PMIDs: 25363760, 27824329, 28191889, 28263302, 33004838, 33057194), but the maximum score for genetic evidence (12 points) has been reached. One de novo missense variant (PMID: 25621899) with evidence of loss-of-function (PMID: 31285321) and at least six de novo missense variants of unknown significance (PMIDs: 28135719, 31981491) have also been reported in individuals with neurodevelopmental disorders. The mechanism of pathogenicity is predicted to be loss-of-function based on the protein truncating variants reported in individuals affected with neurodevelopmental disorders and experimental data showing reduced protein expression in cultured cells bearing truncating variants in ANK2 (PMID: 31285321). The gene-disease association is also supported by mouse models and rescue experiments in cultured cells (PMID: 31285321).
Of note, loss-of-function missense variants in ANK2 have also been observed in individuals with long QT syndrome (PMIDs: 15178757, 17242276); the ClinGen Long QT Gene Curation Expert Panel is evaluating the clinical validity of this reported gene-disease relationship.
In summary, there is definitive evidence supporting the relationship between ANK2 and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 21, 2020 (SOP Version 7).
Variants in ANK2 were first reported in humans with autosomal dominant complex neurodevelopmental disorder as early as 2012 (Iossifov et al., PMID: 22542183). Individuals with variants identified in this gene have presented with neurodevelopmental phenotypes including autism spectrum disorder, intellectual disability, seizures, and microcephaly. Evidence supporting this gene-disease relationship includes case-level and experimental data. De novo protein truncating variants in this gene have been reported in over 12 individuals with neurodevelopmental disorders, including 8 probands from 7 publications (PMIDs: 22542183, 25363768, 27479843, 28554332, 30564305, 30755392, 31981491) that are included in this curation, and 5 additional probands (PMIDs: 33004838 [3 individuals], 33057194 [2]) not scored since the maximum points had been reached. In addition, 10 protein truncating variants of unknown inheritance have also been reported in individuals with neurodevelopmental disorders (PMIDs: 25363760 [2], 28191889 [6], 28263302 [1], 27824329 [1]). One de novo missense variant (PMID: 25621899) with evidence of loss-of-function (PMID: 31285321) and at least six de novo missense variants of unknown significance (PMIDs: 28135719 [(2]), 31981491 [(4])) have also been reported in individuals with neurodevelopmental disorders. The mechanism for disease is predicted to be haploinsufficiency based on the protein truncating variants reported in individuals affected with neurodevelopmental disorders and experimental data showing reduced protein expression in cultured cells bearing truncating variants in ANK2 (PMID: 31285321). The gene-disease association is also supported by mouse models and rescue experiments in cultured cells (PMID: 31285321). Of note, loss-of-function missense variants in ANK2 have also been observed in individuals with Long QT syndrome (PMIDs: 15178757,17242276); the ClinGen Long QT GCEP is evaluating the clinical validity of this reported gene-disease relationship. In summary, there is sufficient evidence to support a definitive gene-disease relationship between ANK2 and complex neurodevelopmental disorder. The classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 10/21/20 (SOP Version 7).
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