Shared and distinct phenotypic profiles among neurodevelopmental disorder genes

Area of Science:

• Genetics and Genomics
• Neuroscience
• Developmental Biology

Background:

• Neurodevelopmental disorders (NDDs), including intellectual disability (ID), autism spectrum disorder (ASD), epilepsy (EP), and cerebral palsy (CP), are linked to rare pathogenic variants in numerous genes.
• These NDDs often co-occur and share genetic underpinnings, but the full spectrum of phenotypic effects and the balance of shared versus distinct genetic influences are not fully understood.

Purpose of the Study:

• To investigate neurodevelopmental disorder (NDD) genes across four diagnostic categories (ID, ASD, EP, CP) using a cross-disorder framework.
• To characterize gene-associated phenotypic profiles and identify convergent biological pathways influencing clinical outcomes.
• To provide a framework for refining therapeutic strategies and improving prognostication for individuals with pathogenic variants in NDD genes.

Main Methods:

• Phenotype-based gene clustering was performed on a discovery cohort of 8,973 probands with pathogenic variants in 263 NDD genes.
• Six distinct gene clusters were identified, revealing patterns of genetic overlap across NDD diagnostic categories.
• An independent validation cohort of 19,704 probands was used to replicate the identified gene clusters. Gene Ontology enrichment analyses were conducted.

Main Results:

• Six distinct gene clusters were identified, demonstrating structured patterns of genetic overlap and preferential contribution to specific NDD combinations (ID, ASD, EP, CP).
• The largest cluster was primarily associated with ID, while others showed enrichment for combinations like ASD and ID, or EP and ID, with varying frequencies.
• Five of the six clusters were successfully replicated in an independent cohort, and distinct biological processes were associated with each cluster.

Conclusions:

• Neurodevelopmental disorder (NDD) genes form coherent clusters that consistently map to characteristic phenotypic profiles.
• These findings highlight shared and distinct genetic influences across different NDDs, suggesting specific molecular mechanisms underlie varied diagnostic presentations.
• The identified gene clusters offer a framework to guide future therapeutic development and enhance early prognostication for individuals affected by NDDs.