Exome sequencing and diffusion tensor imaging in developmental disabilities

Abstract

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 months, 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. Novel, nonsynonymous variants in the patients were then looked for within this subset of genes and in known IDD genes. Results Seven novel, nonsynonymous (all of them were heterozygous, missense) variants belonged to ultra-conserved genes that are known to cause abnormal brain morphology in mutant mice. Similarly, 3 novel, nonsynonymous (all of them were heterozygous, missense) variants belonged to known IDD genes. Two patients with underdeveloped arcuate fasciculus contained novel, nonsynonymous variants in genes (MID1 and EN2) regulating axon guidance pathway. Conclusions Exome sequencing identified several new the genetic causes of IDD.

Relationship between genotype and arcuate fasciculus morphology in six young children with global developmental delay: Preliminary DTI stuy

“…The detailed method of identification of genetic mutations was previously published (16). We describe the procedure briefly here.…”

“…The argument of i having the most probable a posteriori probability P(fiber j ∣C i ) determines the membership of the streamline tract, fiber j . Details of the DWI-MAP classifier are available in our previous study (16). …”

“…For example, several rare mutations of axon guidance pathways that are known to cause primary white matter abnormality have been described (15). Indeed, in a recent study utilizing DWI and whole exome sequencing, we showed that mutations in two genes (EN2 and MID1) involving axon guidance pathways were associated with poorly developed AF in children with GD (16). In the same study, we also identified mutations in other genes whose relationship to white matter abnormalities is less obvious (16).…”

“…Indeed, in a recent study utilizing DWI and whole exome sequencing, we showed that mutations in two genes (EN2 and MID1) involving axon guidance pathways were associated with poorly developed AF in children with GD (16). In the same study, we also identified mutations in other genes whose relationship to white matter abnormalities is less obvious (16). Thus, the mutations may not only cause primary white matter abnormalities (if present in axon guidance pathway genes) or secondary white matter abnormalities.…”

“…However, in our previous study (16), we used a relatively simplistic classification scheme in which patients with GD were classified into those with and without identifiable AF on DWI tractography. Subsequent to that study, the present study re-analyzed these data using novel diffusion weighted imaging (DWI) analytical techniques such as high-resolution tracking of individual branches of AF called “DWI-based maximum a posteriori probability (DWI-MAP) classifier (17)” to automatically detect separate language pathway branches connecting four distinct language areas such as Broca’s area for speech, Wernicke’s area for comprehension, inferior parietal area for reading, and premotor area for fluency (8, 18, 19).…”