Whole exome sequencing reveals pathogenic variants in KL and PUDP genes as the cause of intellectual disability in an Iranian family

Abstract

Intellectual disability (ID) is a common neurological disease which is diagnosed by the low-level of intelligence quotient (<70). Up to the present time, numerous genes with various inheritance patterns have been identified as the potential causes of ID. However, hitherto, the underlying molecular mechanism of the majority of these cases has remained unrecognized. Hence, the present study employed a family-based whole exome sequencing (WES) approach to identify causal variants of ID in a consanguineous first cousin Iranian family. For the first time, a homozygote pathogenic missense variant was identified in Klotho (KL) gene (NM_004795.4; c.2069 T > C; p.P690L) in ID patients. Moreover, a novel hemizygote missense X-linked variant was recognized in PUDP gene (NM_001135565.2; c. 97 G> A; p.E33K). These missense variants are likely to be responsible for ID because any malfunction in Klotho protein can lead to defects in voltage-gated calcium channel and consequently cause damages in the neurons. In addition, any flaw in the protein coded by PUDP gene brings about not only a deficiency in binding of magnesium to NMDA receptor but also an overstimulation of neurons and their damage. This study provides beneficial information for the diagnosis of ID patients. Furthermore, these findings suggest that PUDP and KL genes are associated with brain development. Finally, this study not only sheds light on the underlying pathobiology of ID but also supports the application of WES in the identification of novel variants in neurodevelopmental disorders.