PTBP1: A candidate gene for intellectual disability

Intellectual disability (ID) is a common heterogeneous disease. Many genes have been implicated in the etiology of ID, yet gene discovery continues at a fast pace. In this study, we investigated the genetic cause of ID in a consanguineous Arab family. For that purpose we utilized autozygosity mapping, candidate gene testing, and whole exome sequencing to find the causative mutation. We identified a synonymous mutation, c.708C > T, in the polypyrimidine tract binding protein 1 (PTBP1) gene that fully segregated with the ID phenotype; Mutationtaster predicted the mutation to be disease causing. Analysis of the mutation revealed its effect on an exonic splice enhancer suggesting a change in the potential binding to its target sequence. This mutation was not found in 514 ethnically matched chromosomes and only one allele harbored the same mutation out of 120,782 alleles in the Exome Aggregation Consortium (ExAC) database. PTBP1 plays a major role in splicing related to neuronal differentiation; its repressive activity regulates activation of a brain specific alternative splicing program. This is the first study to implicate a PTBP1 mutation in human disease.