Identification of novel variants in sixteen Iranian patients with intellectual disability by targeted next-generation sequencing

Background: Intellectual disability (ID) is one of the most common cognitive disorders affecting 1-3% of the general population. Both of environment and genetic factors is involved in etiology of ID. Diagnosis of ID by cytogenetic and molecular routine methods is difficult because of its extensive genetic heterogeneity. However, the advent of NGS has simplified the identification of mutations in ID-related genes.Methods: In this study we performed NGS for 16 Iranian patients with ID. Via using a custom NimbleGen chip capturing, samples were screened for mutations in 514 genes that associated with pathogenesis of ID according to NGS approach.Result: By using the targeted sequencing, we identified one causative gene in 1 of 16 patients. The variant of this gene (PAH-c.727C> T) was previously determined pathogen. Furthermore, 11 novel variants were identified that CDK5RAP2, C5orf42 and CDH15 genes were the most common ID-related genes. These variants were CDK5RAP2-c.171A> G, CDK5RAP2-c.580C> T, CDK5RAP2-c.1136T> A, CDK5RAP2-c.1946C> G, C5orf42-c.2911A> G, C5orf42-c.3358A> G, C5orf42-c.9367C> T, C5orf42-c.7979G> A, C5orf42-c.7400+7C> G, CDH15-c.1211C> T and CDH15-c.1251C> T. Also, all of the identified candidate causing-disease variants have been confirmed by direct sequencing. More analysis of this variants demonstrated that NLRP3-c.1695T> A and DPAGT1-c.85A> T are likely pathogen.Conclusion: The present study showed that target NGS as a novel, highly-sensitive and rapid screening approach is facilitated the diagnosis of ID. Targeted sequencing due to selectable genes, affordable costs and high sequencing coverage has the advantage to better diagnosis of this heterogeneous disorder. Finally, we suggest that functional studies be conducted for these variants to determine whether these variants are cause of ID.

کلیدواژه ها:

Intellectual disability ، Targeted sequencing ، Next generation sequencing ، NGS ، ID ، ID-related genes ، Mental retardation ، Novel variants