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AUTS2 protein interacts with p300, encoded by <jats:italic>EP300<\/jats:italic>, through the HX repeat domain of AUTS2, thereby activating transcription. We previously reported two de novo variants in the HX repeat domain of <jats:italic>AUTS2<\/jats:italic>. These variants disrupt the AUTS2\u2010P300 interaction, resulting in a phenotype resembling Rubinstein\u2010Taybi Syndrome (RSTS) associated with variants in <jats:italic>EP300\/CREBBP<\/jats:italic>. Here, we expand beyond the initial clinical description to delineate the HX domain\u2010associated phenotype and compare it to the AUTS2\u2010haploinsufficient phenotype. We reviewed clinical data, photographs, and neuroimaging studies to examine genotype\u2013phenotype relationships. Our review of 80 individuals included 14 individuals we present here and 66 individuals with <jats:italic>AUTS2<\/jats:italic> variants presented in the literature. The clinical features for individuals with variants in the HX repeat domain include severe intellectual disability, severe language disability, distinct craniofacial and skeletal dysmorphic features, and neuroimaging findings. Facial dysmorphisms include wide and prominent nasal bridges with complex nasal shapes and dysmorphic eyebrows. Dysmorphisms include digit anomalies: Symphalangism and hypoplasia of distal phalanges, exclusive to the HX domain variant group. Cerebellar anomalies not seen with other <jats:italic>AUTS2<\/jats:italic> variants are seen within this group. Our report delineates a distinct and severe clinical phenotype associated with variants in the AUTS2 HX domain, including an in\u2010depth comparison with the AUTS2 haploinsufficiency phenotype features.<\/jats:p>","DOI":"10.1002\/ajmg.a.64093","type":"journal-article","created":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T06:43:00Z","timestamp":1746254580000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Further Delineation of the AUTS2 HX Repeat Domain\u2010Related Phenotype"],"prefix":"10.1002","volume":"197","author":[{"given":"Esin Nur","family":"Erdogan","sequence":"first","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi Vicky","family":"Cheng","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5033-7854","authenticated-orcid":false,"given":"Stefano G.","family":"Caraffi","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit Azienda USL\u2010IRCCS di Reggio Emilia  Reggio Emilia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Ivanovski","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit Azienda USL\u2010IRCCS di Reggio Emilia  Reggio Emilia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Piatelli","sequence":"additional","affiliation":[{"name":"Dipartimento Integrato Neuroscienze Mediche e Chirurgiche e Riabilitazione\u2014Continuit\u00e0 Cure; U.O.C. 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