PT  - JOURNAL ARTICLE
AU  - Cian Murphy
AU  - Ismail Moghul
AU  - Nikolas Pontikos
AU  - Phenopolis consortium, UK Inherited Retinal Dystrophy consortium, UCLex consortium
AU  - Jing Yu
TI  - Phenogenon: Gene to Phenotype Associations for Rare Genetic Diseases
AID  - 10.1101/367292
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 367292
4099  - http://biorxiv.org/content/early/2018/07/11/367292.short
4100  - http://biorxiv.org/content/early/2018/07/11/367292.full
AB  - As genome sequencing is increasingly applied to molecular diagnosis of rare Mendelian disorders, large number of patients with diverse phenotypes have their genomic and phenotypic data pooled together to uncover new genotype - phenotype relations. We introduce Phenogenon, a method that combines: the power of Human Phenotype Ontology for describing patient phenotypes, gnomAD for estimating rare variant population frequency, and CADD for variant pathogenicity prediction. By using a divide and conquer approach, we demonstrate here that Phenogenon is able to uncover true gene to phenotype relations, such as “ABCA4 – Macular dystrophy” and “SCN1A – Seizures”. Additionally, it accurately infers mode of inheritance, such as a recessive mode of inheritance in the case of the “ABCA4 – Macular dystrophy” relationship and a dominant mode of inheritance with the “SCN1A – Seizures” relationship. We also found that CADD has more power to detect early-onset rare genetic diseases than late-onset diseases. In this study, we ran Phenogenon against a diverse cohort of 3288 patients. Among the top 13 gene-phenotype relations, seven were previously known. We also highlight four potentially novel gene – phenotype relations such as “SIPA1L3 – Abnormal electroretinogram”.