Exome sequencing and diffusion tensor imaging in developmental disabilities.

Background: We had previously shown that arcuate fasciculus is poorly developed in patients with intellectual and developmental disabilities (IDD) using diffusion tensor imaging (DTI). In the present study, we used exome sequencing to identify the candidate variants in IDD patients with and without DTI abnormalities.

Methods: Eighteen children with IDD (age: 67 ± 36 mo, 9 females) were included in the present study. The DTI was used to determine the integrity of arcuate fasciculus. The next-generation sequencing was performed on the Solid 4 platform. A novel, analytical strategy was developed to identify a set of candidate genes of interest. We then searched for novel, nonsynonymous variants in the patients within this subset of genes and in known IDD genes.

Results: Seven novel, nonsynonymous (all of them were heterozygous, missense) variants belonged to ultraconserved genes that are known to cause abnormal brain morphology in mutant mice. Similarly, three novel, nonsynonymous (all of them were heterozygous, missense) variants belonged to known IDD genes. Two patients with underdeveloped arcuate fasciculus had novel, nonsynonymous variants in genes (MID1 and EN2) regulating axon guidance pathway.

Conclusion: Exome sequencing identified several new genetic causes of IDD.