Regulatory de novo mutations underlying intellectual disability.

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Genomic Medicine

Background:

• The genetic causes of intellectual disability (ID) are not fully understood, with de novo mutations (DNMs) in coding genes explaining up to 40% of cases.
• The role of regulatory DNMs in the etiology of ID remains largely unexplored.

Purpose of the Study:

• To investigate the role of regulatory de novo mutations (DNMs) in the genetic aetiology of intellectual disability (ID).
• To identify specific regulatory elements and genes affected by DNMs in ID patients.

Main Methods:

• Whole-genome sequencing of 21 ID probands and their parents, plus analysis of 30 additional exome-negative ID genomes.
• Functional validation using luciferase assays to assess enhancer activity and CRISPR-mediated editing to study gene expression effects.
• Bioinformatic analysis to identify enrichment of DNMs in fetal brain-specific enhancers and their association with relevant genes.

Main Results:

• Regulatory DNMs were found to be enriched in fetal brain-specific enhancers compared to adult brain enhancers.
• Mutated enhancers were associated with genes preferentially expressed in the prefrontal cortex.
• Recurrently mutated enhancer clusters regulating nervous system development genes (CSMD1, OLFM1, POU3F3) were identified.
• Most DNMs exhibited allele-specific enhancer activity, and their disruption affected target gene expression.

Conclusions:

• De novo mutations (DNMs) in fetal brain-specific enhancers play a significant role in the aetiology of intellectual disability (ID).
• These findings expand our understanding of the genetic landscape of ID beyond protein-coding mutations.
• Regulatory elements in the fetal brain are critical targets for understanding neurodevelopmental disorders.