RT Journal Article
SR Electronic
T1 Phenogenon: Gene to Phenotype Associations for Rare Genetic Diseases
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 367292
DO 10.1101/367292
A1 Cian Murphy
A1 Ismail Moghul
A1 Nikolas Pontikos
A1 Phenopolis consortium, UK Inherited Retinal Dystrophy consortium, UCLex consortium
A1 Jing Yu
YR 2018
UL http://biorxiv.org/content/early/2018/07/11/367292.abstract
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”.