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Alternative splicing gives rise to three ankyrin\u2010G isoforms comprising different domains with distinct expression patterns. Mono\u2010 or biallelic <jats:italic>ANK3<\/jats:italic> variants are associated with non\u2010specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic <jats:italic>ANK3<\/jats:italic> variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity\/self\u2010injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono\u2010 and biallelic variants appear to be localized differently across the three different ankyrin\u2010G isoforms, suggesting isoform\u2010specific pathological mechanisms.<\/jats:p>","DOI":"10.1111\/cge.14587","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T07:54:46Z","timestamp":1720684486000},"page":"574-584","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The phenotypic and genotypic spectrum of individuals with mono\u2010 or biallelic <i>ANK3<\/i> variants"],"prefix":"10.1111","volume":"106","author":[{"given":"Francesca","family":"Furia","sequence":"first","affiliation":[{"name":"Department of Epilepsy Genetics and Personalized Treatment The Danish Epilepsy Centre  Dianalund Denmark"},{"name":"Faculty of Health Science University of Southern Denmark (SDU)  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda M.","family":"Levy","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Kennedy Center, Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miel","family":"Theunis","sequence":"additional","affiliation":[{"name":"Center for Human Genetics University Hospitals Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Bamshad","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Genetic Medicine University of Washington  Seattle Washington USA"},{"name":"Brotman\u2010Baty Institute for Precision Medicine University of Washington  Seattle Washington USA"},{"name":"Department of Pediatrics, Division of Genetic Medicine Seattle Children's Hospital  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan N.","family":"Bartos","sequence":"additional","affiliation":[{"name":"Department of Genetics The University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia K.","family":"Bijlsma","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Leiden University Medical Centre  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Brancati","sequence":"additional","affiliation":[{"name":"Human Genetics, Department of Life, Health and Environmental Sciences University of L'Aquila  L'Aquila Italy"},{"name":"Human Functional Genetics Laboratory Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Roma  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Cejudo","sequence":"additional","affiliation":[{"name":"CHU de Poitiers Service de G\u00e9n\u00e9tique  Poitiers France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1616-2448","authenticated-orcid":false,"given":"Jessica X.","family":"Chong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Genetic Medicine University of Washington  Seattle Washington USA"},{"name":"Brotman\u2010Baty Institute for Precision Medicine University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"De Luca","sequence":"additional","affiliation":[{"name":"Human Genetics, Department of Life, Health and Environmental Sciences University of L'Aquila  L'Aquila Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah Joy","family":"Dean","sequence":"additional","affiliation":[{"name":"Department of Genetics The University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Egense","sequence":"additional","affiliation":[{"name":"Division of Genomic Medicine, Department of Pediatrics University of California Davis  Sacramento California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himanshu","family":"Goel","sequence":"additional","affiliation":[{"name":"General Genetics Service Hunter Genetics  Waratah New South Wales Australia"},{"name":"School of Medicine and Public Health College of Health, Medicine and Wellbeing, University of Newcastle  Callaghan New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Guenzel","sequence":"additional","affiliation":[{"name":"GeneDx Inc.  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