Genetic variants in Rps4x cause intellectual disability with dysmorphic features, microcephaly, and autism

Abstract

X-linked intellectual disability (XLID) comprises a group of heterogeneous disorders associated with impaired cognitive function and developmental delays. It has been estimated that 10% of the genes on the X-chromosome are associated with at least one form of intellectual disability. To date, genetic variants in 172 genes have been associated with XLID. Clinically, these disorders are highly variable, with some exhibiting multi-system involvement and others limited only to intellectual impairment. Here we describe a new XLID condition caused by defects in RPS4X, which encodes a component of the small (40S) subunit of the ribosome. Genetic testing of two male siblings with dysmorphic facial features, microcephaly, global developmental delay, and autism revealed a maternally inherited missense variant in RPS4X. Studies in patient fibroblasts and zebrafish indicate this RPS4X variant is pathogenic, with functional findings consistent with the clinical presentation. Four additional individuals with intellectual disability were identified through the GeneMatcher and the 100,000 Genomes project that also bear RPS4X variants. Together, these data support RPS4X as a new XLID-associated gene, expanding the involvement of ribosomal components in genetic disease.

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Item Type:	Article
Authors/Creators:	Matheny-Rabun, C. Holloway, L. Corning, K. Louie, R. Lu, P. Smol, T. Boussion, S. Woods, E. Johnson, D. Williams, C. Steet, R. Friez, M. Arno, G. Stevenson, R. Flanagan-Steet, H.
Copyright, Publisher and Additional Information:	© The Author(s) 2026. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/bync-nd/4.0/.
Keywords:	Diseases; Genetics
Dates:	Submitted: 14 May 2025 Accepted: 14 April 2026 Published (online): 24 April 2026 Published: 24 April 2026
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield)
Date Deposited:	13 Jul 2026 16:00
Last Modified:	13 Jul 2026 16:00
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41525-026-00573-0
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:243080

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Genetic variants in Rps4x cause intellectual disability with dysmorphic features, microcephaly, and autism

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