{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T22:43:32Z","timestamp":1785365012422,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T00:00:00Z","timestamp":1629417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/genes12081275","type":"journal-article","created":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T21:47:52Z","timestamp":1629668872000},"page":"1275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1174-2806","authenticated-orcid":false,"given":"Pleuntje J.","family":"van der Sluijs","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u00eblle","family":"Alders","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J. M.","family":"Dingemans","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4806-9571","authenticated-orcid":false,"given":"Kareesma","family":"Parbhoo","sequence":"additional","affiliation":[{"name":"Division of Genetic & Genomic Medicine, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bregje W.","family":"van Bon","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer C.","family":"Dempsey","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9377-028X","authenticated-orcid":false,"given":"Dan","family":"Doherty","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Washington, Seattle, WA 98195, USA"},{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute, Seattle, WA 98101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6304-1710","authenticated-orcid":false,"given":"Johan T.","family":"den Dunnen","sequence":"additional","affiliation":[{"name":"Human Genetics and Clinical Genetics, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica H.","family":"Gerkes","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilana M.","family":"Milller","sequence":"additional","affiliation":[{"name":"Rare Disease Institute, Children\u2019s National Hospital, Washington, DC 20010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4783-8674","authenticated-orcid":false,"given":"Stephanie","family":"Moortgat","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique Humaine, Institut de Pathologie et de G\u00e9n\u00e9tique, 6041 Gosselies, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra S.","family":"Regier","sequence":"additional","affiliation":[{"name":"Rare Disease Institute, Children\u2019s National Hospital, Washington, DC 20010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia A. L.","family":"Ruivenkamp","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betsy","family":"Schmalz","sequence":"additional","affiliation":[{"name":"Division of Genetic & Genomic Medicine, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0119-5896","authenticated-orcid":false,"given":"Thomas","family":"Smol","sequence":"additional","affiliation":[{"name":"EA7364 RADEME, Institut de G\u00e9n\u00e9tique M\u00e9dicale, Universit\u00e9 de Lille, CHU de Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyra E.","family":"Stuurman","sequence":"additional","affiliation":[{"name":"Erasmus MC, Department of Clinical Genetics, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Vincent-Delorme","sequence":"additional","affiliation":[{"name":"EA7364 RADEME, Universit\u00e9 de Lille, Clinique de G\u00e9n\u00e9tique, CHU de Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert B. A.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bekim","family":"Sadikovic","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre and London Health Sciences Centre, Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott E.","family":"Hickey","sequence":"additional","affiliation":[{"name":"Division of Genetic & Genomic Medicine, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5664-7987","authenticated-orcid":false,"given":"Jill A.","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Baylor Genetics Laboratories, Houston, TX 77021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7170-8186","authenticated-orcid":false,"given":"Isabelle","family":"Maystadt","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique Humaine, Institut de Pathologie et de G\u00e9n\u00e9tique, 6041 Gosselies, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gijs W. E.","family":"Santen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.ajhg.2012.02.007","article-title":"Haploinsufficiency of ARID1B, a member of the SWI\/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability","volume":"90","author":"Hoyer","year":"2012","journal-title":"Am. J. Hum. 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