Further Delineation of the AUTS2 HX Repeat Domain‐Related Phenotype

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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Publication Details

Journal
American Journal of Medical Genetics Part A
Published
2025-05-03
DOI
https://doi.org/10.1002/ajmg.a.64093
Citations
2
Primary Topic
Genetics and Neurodevelopmental Disorders
Type
article
Field-Weighted Citation Impact
3.63

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article

Further Delineation of the AUTS2 HX Repeat Domain‐Related Phenotype

Nataliya Di Donato, M. Pauly, Kimberly A. Aldinger, Arie van Haeringen et al.
2 citations
American Journal of Medical Genetics Part A
Genetics and Neurodevelopmental Disorders
3.63
article

Further Delineation of the AUTS2 HX Repeat Domain‐Related Phenotype

Nataliya Di Donato, M. Pauly, Kimberly A. Aldinger, Arie van Haeringen, Ping Yee Billie Au, Livia Garavelli, Michael Scott Perry, Andrew Swale, Georgia Vasileiou, Ivan P. Ivanovski, Joshua Rotenberg, Joseph Porrmann, Shaydah Kheradmand, Michael C. Kruer, Gianluca Piatelli, Edoardo Errichiello, Orsetta Zuffardi, William B. Dobyns, Stefano Giuseppe Caraffi, Jennifer B. Humberson, Chi Vicky Cheng, Helen Magee, Scott E. Hickey, Claudia Ruivenkamp, Michael Schneider, Caren Landes, Antigone Papavasiliou, Bradley Prince, Daniel C. Koboldt, Somayeh Bakhtiari, Thomas Leis, Astrid Weber, André Reis, Esin Nur Erdogan
article en
2 citations

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.

American Journal of Medical Genetics Part AVol. 197(9)
University of Minnesota (US), Nationwide Children's Hospital (US), Barrow Neurological Institute (US), University of Arizona (US), University of Liverpool (GB), Columbus State Community College (US), University of Calgary (CA), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), University of Washington (US), Memorial Hermann Memorial City Medical Center (US), University of Pavia (IT), Leiden University Medical Center (NL), Istituto Giannina Gaslini (IT), Alberta Children's Hospital (CA), Universitätsklinikum Erlangen (DE), Norcliffe Foundation (US), Cook Children's Medical Center (US), Azienda Sanitaria Unità Locale di Reggio Emilia (IT), Liverpool Women's Hospital (GB), Alder Hey Children's NHS Foundation Trust (GB), Phoenix Children's Hospital (US), Istituti di Ricovero e Cura a Carattere Scientifico (IT), St. Christopher's Hospital for Children (US), Iaso Children’s Hospital (GR), Alberta Children's Hospital Research Institute, University of Virginia (US), Technische Universität Dresden (DE)
Wellcome Trust, National Institutes of Health
Quality Education
Openalex Percentile: Top 8%
Genetics and Neurodevelopmental Disorders
3.63
DOISourceOpenAlex
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