Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy

Area of Science:

• Genetics
• Neuroscience
• Rare Diseases

Background:

• Epileptic encephalopathies (EE/DEE) have known Mendelian genetic causes, but their genetic architecture remains incompletely understood.
• Existing research highlights numerous genes associated with EE/DEE, yet a significant portion of cases lack a clear genetic explanation.

Purpose of the Study:

• To investigate the genetic architecture of EE/DEE beyond simple Mendelian inheritance.
• To identify novel genetic factors contributing to EE/DEE by analyzing exome data.

Main Methods:

• Exome sequencing analysis of 743 EE/DEE cases and 2366 controls.
• Statistical analysis to identify overrepresented damaging ultra-rare variants (dURVs) in EE/DEE patients.
• Gene-based analysis to detect significant enrichment of de novo mutations in specific genes.

Main Results:

• Damaging ultra-rare variants (dURVs) unique to individuals were significantly enriched in EE/DEE cases, affecting both known and non-EE/DEE genes.
• Significant enrichment of dURVs in non-EE/DEE genes suggests an oligogenic contribution in a subset of EE/DEE cases.
• Exome-wide significant enrichment of damaging de novo mutations in NF1 was identified in infantile spasms.

Conclusions:

• EE/DEE exhibits genetic complexity, involving contributions from multiple genes and variants beyond simple Mendelian inheritance.
• The findings challenge the view of EE/DEE as solely a collection of Mendelian disorders, highlighting the role of oligogenic and modifier variants.
• This study underscores the importance of considering complex genetic architectures in diagnosing and understanding EE/DEE.