RPS6KA3 – Non-syndromic X-linked Intellectual Disability

In a single multigenerational pedigree, a 584-kb microduplication at Xp22.12 encompassing RPS6KA3 segregated with variable neurodevelopmental phenotypes, including mild intellectual disability in three males and pervasive developmental disorder in one female, consistent with Non-syndromic X-linked intellectual disability (PMID:23985797). The duplication was detected by array-CGH in three brothers, two sisters, and their mother; all four offspring carrying the duplication exhibited cognitive and behavioral deficits, while the mother was unaffected.

No additional unrelated cases have been reported, and functional assays directly assessing the impact of RPS6KA3 copy-number gain on kinase activity or neuronal development in non-syndromic intellectual disability are lacking. Existing immunoblot and kinase assays for Coffin–Lowry syndrome focus on loss-of-function mutations and do not address duplications.

Overall, the ClinGen clinical validity classification for RPS6KA3 in non-syndromic X-linked intellectual disability is Limited based on a single structural variant segregating in one family. Genetic evidence is Tier 2 (Limited): one duplication and four affected individuals; functional evidence is absent. No conflicting evidence has been reported.

Given these data, RPS6KA3 dosage alterations may underlie rare cases of X-linked intellectual disability, but additional case series and mechanistic studies are required. Key take-home: consider RPS6KA3 copy-number analysis in unexplained X-linked intellectual disability.

References

• Journal of Human Genetics • 2013 • An Xp22.12 microduplication including RPS6KA3 identified in a family with variably affected intellectual and behavioral disabilities PMID:23985797

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