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 (  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.