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<p>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 <i>RPS4X</i>, 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 <i>RPS4X</i>. Studies in patient fibroblasts and zebrafish indicate this <i>RPS4X</i> 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 <i>RPS4X</i> variants. Together, these data support <i>RPS4X</i> as a new XLID-associated gene, expanding the involvement of ribosomal components in genetic disease.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月24日

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  • Courtney Matheny-Rabun,
  • Lynda Holloway,
  • Ken Corning,
  • Raymond Louie,
  • PoNien Lu,
  • Thomas Smol,
  • Simon Boussion,
  • Emily Woods,
  • Diana Johnson,
  • Catherine Williams,
  • Richard Steet,
  • Michael Friez,
  • Gavin Arno,
  • Roger Stevenson,
  • Heather Flanagan-Steet

摘要

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.