De novo mutations in regulatory elements in neurodevelopmental disorders

Area of Science:

• Genetics
• Developmental Biology
• Genomic Regulation

Background:

• Previously, 42% of severe developmental disorder cases were linked to de novo mutations in coding sequences.
• The role of de novo mutations in regulatory elements remains largely unexplored.
• Regulatory elements control gene expression and are crucial for development.

Purpose of the Study:

• To investigate the contribution of de novo mutations in regulatory elements to developmental disorders.
• To identify specific types of regulatory elements enriched for mutations in affected individuals.
• To estimate the prevalence and impact of these mutations in neurodevelopmental disorders.

Main Methods:

• Analysis of de novo mutations in three classes of putative regulatory elements in nearly 8,000 patients.
• Assessment of evolutionary conservation and functional activity (fetal brain-active elements).
• Statistical analysis to determine enrichment and estimate mutation rates.

Main Results:

• De novo mutations in highly conserved, fetal brain-active elements are significantly enriched in neurodevelopmental disorders.
• A twofold enrichment of recurrently mutated elements was observed.
• An estimated 1-3% of patients without coding variants carry pathogenic de novo mutations in these regulatory elements.

Conclusions:

• De novo mutations in regulatory elements, especially conserved fetal brain-active ones, are an important genetic cause of neurodevelopmental disorders.
• This finding expands the understanding of genetic underpinnings beyond coding regions.
• Combining functional and evolutionary data is crucial for identifying regulatory causes of genetic disorders.