WDR13 – X‑linked Intellectual Disability

WDR13 has been implicated in X‑linked intellectual disability (XLID) through robust genetic and functional studies. Evidence from multi‑patient investigations has nominated WDR13 as a candidate gene for XLID, with observations in families where the variant co‑segregated with disease status (PMID:34946860). This association is supported by the detection of a pathogenic nonsense variant.

The genetic evidence is centered on the identification of a nonsense variant, c.757C>T (p.Arg253Ter), uncovered by X‑chromosome exome sequencing in males with a familial form of intellectual disability (PMID:34946860). Although the precise number of probands has not been exhaustively reported, familial segregation with at least two additional affected relatives strengthens the genetic basis of this association.

Functional studies further validate the pathogenicity of WDR13 variants. Quantitative PCR analysis in patient fibroblasts revealed a significant reduction in WDR13 expression, consistent with a loss‑of‑function mechanism. In addition, earlier investigations offered insights into the gene’s regulatory role through nuclear localization and conserved protein domains, bolstering the link between this variant and the clinical phenotype (PMID:12659815).

In the context of XLID, these converging lines of evidence – genetic findings from exome sequencing and corroborative functional assays – provide a coherent narrative. The isolated c.757C>T (p.Arg253Ter) variant, along with its demonstrated impact on gene expression, underscores a moderate level of confidence in the gene‑disease association.

While additional data from large‐scale deletions and indels in XLID cases exist (PMID:20655035), the focused analyses on WDR13 particularly underscore its clinical relevance. Notably, the effect on neural gene regulation as observed in affected patient cells contributes valuable support for its role in disease pathogenesis.

Key take‑home: The combined genetic and functional evidence for WDR13 – notably the nonsense variant c.757C>T (p.Arg253Ter) and its consequent reduced expression – highlights its utility as a candidate marker for XLID, supporting its integration into diagnostic pipelines and future research endeavors.

References

• American journal of human genetics • 2010 • Fine‑scale survey of X chromosome copy number variants and indels underlying intellectual disability PMID:20655035
• Genes • 2021 • WDR13: A Novel Gene Implicated in Non‑Syndromic Intellectual Disability PMID:34946860
• Genomics • 2003 • A highly conserved human gene encoding a novel member of WD‑repeat family of proteins (WDR13) PMID:12659815

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