Investigation of Genetic Aetiology in Intellectual Developmental Disorder with Trio-Whole Exome Sequencing Approach

Intellectual development disorder (IDD) is a heterogeneous condition, and genetic studies are essential to unravel the underlying cellular pathway for brain development and functioning in its etiology. This study aimed to investigate the possible genetic alterations contributing to IDD by performing next generation sequencing (NGS) in affected individuals and their parents, with a particular focus on the discovery of novel disease-associated genes.

Cases diagnosed with IDD according to DSM-5 criteria, who had normal results in conventional cytogenetic analyses, array comparative genomic hybridization and Fragile X (FMR1) testing, were analyzed by using Trio-Whole Exome Sequencing (Trio-WES). Genomic DNA was extracted, amplicon libraries were generated, and sequencing was conducted on a NGS platform.

We detected pathogenic and/or likely pathogenic variations in MANBA, TLK2, NAA15, CSF1R, DRD4, TRIO genes in 5 of 7 cases included in the study. Protein stability prediction analysis were performed for the p.(Arg339Gln) variant in TLK2 and p.(Asn1406Ser) variant in TRIO gene. Both variants were predicted to reduce protein stability and classified as "destabilizing."

Trio-WES provided a substantial contribution to the molecular diagnosis of IDD. These findings highlight the utility of whole exome sequencing as a powerful tool for uncovering novel disease-associated genes.