Phenogenon

Phenogenon identifies gene-phenotype associations and jointly predicts modes of inheritance by integrating Human Phenotype Ontology (HPO)-annotated patient phenotypes with gnomAD allele population frequencies and CADD scores.

Key Features:

• Data integration: Combines HPO-annotated patient phenotypes with gnomAD allele population frequency and CADD scores for variant pathogenicity assessment.
• Joint inheritance prediction: Predicts mode of inheritance alongside gene-phenotype associations, distinguishing dominant and recessive patterns.
• Large-cohort analysis: Applied to a cohort of 3,290 patients who underwent whole exome sequencing to analyze extensive datasets.
• Validation and discovery: Recapitulated known associations such as "SRD5A3-Abnormal full-field electroretinogram-recessive" and "GRHL2-Nail dystrophy-recessive" and identified potentially novel associations such as "RRAGA-Abnormality of the skin-dominant".

Scientific Applications:

• Molecular diagnosis of rare Mendelian disorders: Supports identification of gene-phenotype links relevant to clinical molecular diagnosis.
• Gene-phenotype discovery across cohorts: Enables discovery of novel gene-phenotype relationships by pooling genetic and phenotypic data from diverse patient populations.

Methodology:

Requires a VCF file containing all samples sorted by chromosome and genomic position for proper indexing and performs statistical analyses integrating HPO, gnomAD, and CADD data to predict gene-phenotype associations.