A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria

Abstract

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses.

The Study of a 231 French Patient Cohort Significantly Extends the Mutational Spectrum of the Two Major Usher Genes MYO7A and USH2A

“…In 2015 was published what would become the international standard for DNA variants' classification, the ACMG/AMP guidelines [13]. These guidelines were meant to be applied to many different genes and conditions, and since then are being continually discussed and adapted [15][16][17][18][19][20].…”

ARID2, a milder cause of Coffin‐Siris Syndrome? Broadening the phenotype with 17 additional individuals

“…In the report by Wang et al (2022), a seemingly unaffected parent was found to have a pathogenic ARID2 change which was passed on to their child; this suggests that there may be additional individuals with ARID2 changes who have few or no symptoms. Van der Sluijs et al (2021) reported ARID1B variants that appeared to be inherited from unaffected or mildly affected parents, further highlighting that this may be the case in other BAFopathy genes. The use of methylation “signatures” is being increasingly utilized to help identify the pathogenicity of certain variants of uncertain significance in BAFopathy genes as well as other genes (Aref‐Eshghi et al, 2020; Haghshenas et al, 2020; Kerkhof et al, 2021).…”

Integration of EpiSign, facial phenotyping, and likelihood ratio interpretation of clinical abnormalities in the re‐classification of an ARID1B missense variant

“…Human‐independent phenotyping methodologies provide non‐biased syndrome correlation to facilitate the interpretation of DNA sequencing data (Dudding‐Byth et al, 2017 ; Hsieh et al, 2022 ), with a role in classifying ARID1B variants (van der Sluijs et al, 2021 ). Both GestaltMatcher and FaceMatch had ARID1B as the top‐ranked gene in the variants from the genomic output.…”

“…Due to ascertainment bias, individuals with a priori diagnosis of ARID1B‐CSS may over‐represent more discernible features (Bogershausen & Wollnik, 2018 ; Santen et al, 2014 ; van der Sluijs et al, 2019 ; Vergano et al, 1993 ). Pathogenic variants may be inherited from a mildly affected parent (Mignot et al, 2016 ; van der Sluijs et al, 2019 , 2021 ). BAF complex disruption is associated with Coffin–Siris and Nicolaides–Baraitser syndromes ( SMARCA2 OMIM #600014; Wolff et al, 2012 ), collectively known as BAFopathies, which include developmental delay, coarse facial features, and phalangeal abnormalities (Aref‐Eshghi et al, 2018 , 2019 ).…”