Phenogenon: Gene to phenotype associations for rare genetic diseases

As high-throughput sequencing is increasingly applied to the molecular diagnosis of rare Mendelian disorders, a large number of patients with diverse phenotypes have their genetic and phenotypic data pooled together to uncover new gene-phenotype relations. We introduce Phenogenon, a statistical tool that combines, Human Phenotype Ontology (HPO) annotated patient phenotypes, gnomAD allele population frequency, and Combined Annotation Dependent Depletion (CADD) score for variant pathogenicity, in order to jointly predict the mode of inheritance and gene-phenotype associations. We ran Phenogenon on our cohort of 3,290 patients who had undergone whole exome sequencing. Among the top associations, we recapitulated previously known, such as "SRD5A3—Abnormal full-field electroretinogram—recessive" and "GRHL2 –Nail dystrophy—recessive", and discovered one potentially novel, “RRAGA–Abnormality of the skin—dominant”. We also developed an interactive web interface available at https://phenogenon.phenopolis.org to visualise and explore the results.