Studies on intellectual disability identify variants in established genes as well as confirm candidature of new genes

Intellectual disability (ID) is a neurodevelopmental disorder, characterized by congenital cognitive and adaptive behavioral issues. We studied multiple patients with ID born to consanguineous parents. Exome sequencing was completed for selected patients and the data were filtered using an allele frequency of less than 0.01. All exonic and splice-site variants were considered. Segregation analyses were performed using allele-specific PCR and Sanger sequencing. Expression analyses of candidate genes were determined after cDNA synthesis from the mouse brain. Clinical evaluations revealed that the patients in the four families exhibited different degrees of cognitive impairments. Patients in two families had no other phenotypes while those from the other two families also manifested disorders such as epilepsy. In family PKID01, a known homozygous missense variant of UFSP2 was found to segregate with the phenotype. We also identified four biallelic novel variants including missense, frameshift, and nonsense variants in ATP13A2, QPCTL, WDR62 and FMO4 in the affected patients from three families. Among these, the QPCTL variant pinpoints a new candidate gene for ID. This study expands the genetic etiology of ID. Intrafamilial genetic heterogeneity underscored the difficulties of molecular characterization of ID in even small nuclear consanguineous families. This research yielded only the second family in literature with a homozygous FMO4 variant, strengthening its candidature with ID.