Journal article
Further Delineation of the AUTS2 HX Repeat Domain‐Related Phenotype
American journal of medical genetics. Part A, v 197(9), e64093
Sep 2025
PMID: 40317680
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Haploinsufficiency of AUTS2 is associated with a neurodevelopmental disorder characterized by intellectual disability, autistic features, and spasticity. AUTS2 protein interacts with p300, encoded by EP300, through the HX repeat domain of AUTS2, thereby activating transcription. We previously reported two de novo variants in the HX repeat domain of AUTS2. These variants disrupt the AUTS2‐P300 interaction, resulting in a phenotype resembling Rubinstein‐Taybi Syndrome (RSTS) associated with variants in EP300/CREBBP. Here, we expand beyond the initial clinical description to delineate the HX domain‐associated phenotype and compare it to the AUTS2‐haploinsufficient phenotype. We reviewed clinical data, photographs, and neuroimaging studies to examine genotype–phenotype relationships. Our review of 80 individuals included 14 individuals we present here and 66 individuals with AUTS2 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 AUTS2 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‐depth comparison with the AUTS2 haploinsufficiency phenotype features.
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Details
- Title
- Further Delineation of the AUTS2 HX Repeat Domain‐Related Phenotype
- Creators
- Esin Nur Erdogan - Norcliffe FoundationChi Vicky Cheng - Norcliffe FoundationStefano G. Caraffi - Azienda Sanitaria Unità Locale di Reggio EmiliaIvan Ivanovski - Azienda Sanitaria Unità Locale di Reggio EmiliaGianluca Piatelli - Istituto Giannina GasliniEdoardo Errichiello - University of PaviaAntigone S. Papavasiliou - Iaso Children’s HospitalGeorgia Vasileiou - Friedrich-Alexander-Universität Erlangen-NürnbergAndré Reis - Friedrich-Alexander-Universität Erlangen-NürnbergBradley Prince - University of CalgaryScott E. Hickey - Nationwide Children's HospitalDaniel C. Koboldt - Nationwide Children's HospitalMichael C. Schneider - St. Christopher's Hospital for ChildrenJoseph Porrmann - Technische Universität DresdenNataliya Di Donato - Technische Universität DresdenThomas Leis - Friedrich-Alexander-Universität Erlangen-NürnbergM. Scott Perry - Cook Children's Medical CenterJennifer Humberson - University of VirginiaJoshua Rotenberg - Memorial Hermann Memorial City Medical CenterSomayeh Bakhtiari - Barrow Neurological InstituteHelen Magee - Barrow Neurological InstituteShaydah Kheradmand - GeneDx, LLCMichael C. Kruer - Barrow Neurological InstituteAndrew Swale - University of LiverpoolAstrid Weber - University of LiverpoolCaren Landes - Alder Hey Children's NHS Foundation TrustOrsetta Zuffardi - University of PaviaLivia Garavelli - Azienda Sanitaria Unità Locale di Reggio EmiliaArie Haeringen - Leiden University Medical CenterClaudia A. L. Ruivenkamp - Leiden University Medical CenterMelissa Pauly - Friedrich-Alexander-Universität Erlangen-NürnbergPing Yee Billie Au - University of CalgaryWilliam B. Dobyns - University of MinnesotaKimberly A. Aldinger (Corresponding Author) - University of Washington
- Publication Details
- American journal of medical genetics. Part A, v 197(9), e64093
- Publisher
- Wiley
- Number of pages
- 10
- Grant note
- National Institutes of Health (1R01NS050375) Wellcome Trust (WT223718/Z/21/Z)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics
- Web of Science ID
- WOS:001480637600001
- Scopus ID
- 2-s2.0-105004196359
- Other Identifier
- 991022197332604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity