Identificazione di una variante missenso nel gene RBM10 in una famiglia sarda con disabilità intellettiva X-linked

摘要

X-linked intellectual disability (XLID) is a heterogeneous disorder, and mutations causing monogenic XLID have now been reported in over 100 genes. We report a five-generation Sardinian family in which seven affected male family members had intellectual disability and craniofacial dysmorphisms. Large-scale next generation exome resequencing of X chromosome genes detected a rare missense variant (c.995G>A, p.Arg332His) located within a highly conserved domain in the RBM10 gene at Xp11.23. Sanger sequencing confirmed the presence of the variant in affected males and in their mothers. The variant was not present in non affected male family members, has not been reported in variant databases and is disease-causing according to a web-based prediction tool. RBM10 is an RNA binding protein involved in the regulation of transcription, alternative splicing and message stabilization. RBM10 nonsense and frameshift mutations are associated with TARP syndrome characterized by Talipes equinovarus, Atrial septal defect, Robin sequence and Persistence of the left superior vena cava and pre- or postnatal lethality in affected males. RBM10 has not been reported in XLID patients until now. Genic intolerance score suggested that RBM10 may be “intolerant” of functional mutations. Although our finding suggest that RBM10 is a reasonable candidate gene for XLID, functional studies and mutations screening in other patients are needed to prove a definite causal relationship between the variant and the phenotype.