Identification of a New Mutation in RSK2, the Gene for Coffin-Lowry Syndrome (CLS), in Two Related Patients with Mild and Atypical Phenotypes.

BACKGROUND: Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked intellectual disability, in which specific associated facial, hand, and skeletal abnormalities are diagnostic features. METHODS: In the present study, an unreported missense genetic variant of the ribosomal S6 kinase 2 (RSK2) gene has been identified, by next-generation sequencing, in two related males with two different phenotypes of intellectual disability (ID) and peculiar facial dysmorphisms. We performed functional studies on this variant and another one, already reported in the literature, involving the same amino acid residue but, to date, without an efficient characterization. RESULTS: Our study demonstrated that the two variants involving residue 189 significantly impaired its kinase activity. CONCLUSIONS: We detected a loss-of-function RSK2 mutation with loss in kinase activity in a three-generation family with an X-linked ID.

TBL1Y: a new gene involved in syndromic hearing loss.

Hereditary hearing loss (HHL) is an extremely heterogeneous disorder with autosomal dominant, recessive, and X-linked forms. Here, we described an Italian pedigree affected by HHL but also prostate hyperplasia and increased ratio of the free/total PSA levels, with the unusual and extremely rare Y-linked pattern of inheritance. Using exome sequencing we found a missense variant (r.206A>T leading to p.Asp69Val) in the TBL1Y gene. TBL1Y is homologous of TBL1X, whose partial deletion has described to be involved in X-linked hearing loss. Here, we demonstrate that it has a restricted expression in adult human cochlea and prostate and the variant identified induces a lower protein stability caused by misfolded mutated protein that impairs its cellular function. These findings indicate that TBL1Y could be considered a novel candidate for HHL.