PERs

PERs identifies pathogenic variant enriched regions across genes and gene families to support interpretation of missense variants and the discovery of essential protein regions conserved among gene family members.

Key Features:

• Gene-family protein sequence alignments: Uses 2,871 gene-family protein sequence alignments encompassing 9,990 genes to analyze conserved regions across related proteins.
• Comprehensive gene-family approach: Leverages conservation among gene family members to pinpoint essential protein regions that may harbor pathogenic missense variants.
• Variant burden analysis: Performs burden analyses comparing 2,219,811 general population variants and 76,153 patient-derived missense variants within the gene-family context.
• Identification of essential regions: Identified 465 novel essential protein regions spanning 41,463 amino acids across 1,252 genes, contrasting with fewer regions detected by gene-wise analyses.
• Enrichment analysis: Reports an 8.33-fold enrichment of de novo patient variants from neurodevelopmental disorder cases versus unaffected siblings (p < 2.72 × 10^-11).
• Pathogenicity assessment using ClinVar: Shows missense variants within identified regions are 106-fold more likely to be classified as pathogenic than benign (OR = 106.15, p < 2.2 × 10^-16).

Scientific Applications:

• Genetic disorder research: Identification of pathogenic variant hotspots to investigate the molecular basis of diseases, notably neurodevelopmental disorders.
• Variant interpretation: Support for classification of missense variants to improve clinical and diagnostic assessments.
• Protein function analysis: Delineation of essential protein regions to inform studies of protein structure–function relationships.

Methodology:

Uses 2,871 gene-family protein sequence alignments and burden analyses comparing 2,219,811 general population variants and 76,153 patient-derived missense variants, with statistical enrichment testing and ClinVar-based odds ratio calculations.