Regulatory de novo mutations underlying intellectual disability

Abstract

The genetic aetiology of a major fraction of patients with intellectual disability (ID) remains unknown. De novo mutations (DNMs) in protein-coding genes explain up to 40% of cases, but the potential role of regulatory DNMs is still poorly understood. We sequenced 63 whole genomes from 21 ID probands and their unaffected parents. In addition, we analysed 30 previously sequenced genomes from exome-negative ID probands. We found that regulatory DNMs were selectively enriched in fetal brain-specific enhancers as compared with adult brain enhancers. DNM-containing enhancers were associated with genes that show preferential expression in the prefrontal cortex. Furthermore, we identified recurrently mutated enhancer clusters that regulate genes involved in nervous system development (CSMD1,OLFM1, andPOU3F3). Most of the DNMs from ID probands showed allele-specific enhancer activity when tested using luciferase assay. Using CRISPR-mediated mutation and editing of epigenomic marks, we show that DNMs at regulatory elements affect the expression of putative target genes. Our results, therefore, provide new evidence to indicate that DNMs in fetal brain-specific enhancers play an essential role in the aetiology of ID.

Evolutionary innovation in conserved regulatory elements across the mammalian tree of life

“…Genetic variation in the enhancer sequences of pleiotropic genes has been associated with trait variation in many contexts. For instance, mutations in enhancer sequences have been found to affect traits important in local adaptation [Chan et al 2009, Wooldridge et al 2022], and to affect human phenotypes with medical relevance [Benko et al 2009, De Vas et al 2023].…”