DNENRICH

DNENRICH performs gene set enrichment analysis of de novo mutations identified through exome sequencing to detect enriched genes and pathways implicated in neurodevelopmental disorders such as schizophrenia.

Key Features:

• Gene Set Enrichment Analysis: Calculates enrichment of predefined gene sets using observed de novo mutations.
• Statistical Significance Estimation: Computes statistical significance for enrichment of small de novo mutations (one or a few nucleotides) within disease cohorts.
• Exome Sequencing Input: Operates on de novo variants typically identified through exome sequencing.
• Synaptic and Pathway Focus: Detects enrichment in synaptic proteins and pathways, including glutamatergic postsynaptic proteins, ARC and NMDAR complexes, targets of fragile X mental retardation protein (FMRP), and regulators of actin filament dynamics.
• Validation Alignment: Aligns enrichment findings with case-control study results for validation.

Scientific Applications:

• Schizophrenia Research: Identifies disproportionate enrichment of small de novo mutations in glutamatergic postsynaptic proteins and complexes such as ARC and NMDAR relevant to schizophrenia aetiology.
• Comparative Neurodevelopmental Genetics: Reveals overlapping mutation-enriched synaptic pathways between schizophrenia, autism, and intellectual disability to inform shared pathophysiology.
• Synaptic Mechanism Elucidation: Highlights mutations in proteins that modulate synaptic strength, including actin filament regulators and FMRP targets, to prioritize molecular mechanisms for follow-up.

Methodology:

Performs gene set enrichment analysis and computes statistical significance for de novo mutations (typically from exome sequencing) and aligns results with case-control study data for validation.