Abstract
The genetic aetiology of a large proportion of intellectual disability (ID) cases still remains undiagnosed as de novo mutations (DNMs) in protein coding regions of the genome explain only 35-40% of the cases1,2. We sequenced whole genomes of 70 individuals, including 24 ID probands, to identify potentially pathogenic DNMs at distal cis-regulatory elements, as they may explain some of these genetically undiagnosed ID cases. In our cohort, DNMs were significantly enriched in fetal brain specific enhancers that were intolerant to mutations within the human population. The majority of these enhancer DNMs showed a significant effect on enhancer activity compared to the reference alleles when tested using luciferase reporter assays. Furthermore, CRISPR interference of CSMD1 enhancer resulted in overexpression of the neurogenesis gene CSMD1 suggesting that the disruption of a transcriptional repressor binding site due to an enhancer DNM could be a potential cause of ID in one of the patients. Taken together, our results demonstrate that DNMs in tissue specific enhancers play an important role in the aetiology of ID.
