Phenogenon: Gene to phenotype associations for rare genetic diseases

Abstract

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.

Clinical and genetic characteristics of 10 Japanese patients with PROM1‐associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population

“…Genomic DNA was extracted from all affected subjects and unaffected family members (where available for co‐segregation analysis). Whole‐exome sequencing with target analysis of retinal disease‐associated genes (RetNet https://sph.uth.edu/retnet/) was performed according to the previously published methods (Fujinami et al, 2016; Oishi et al, 2016; Pontikos et al, 2020; Yang et al, 2020). The identified variants were filtered using allele frequency (less than 1%) in the Human Genetic Variation Database (HGVD; http://www.hgvd.genome.med.kyoto-u.ac.jp/), which provides allele frequencies of the general Japanese population.…”

“…Whole-exome sequencing with target analysis of retinal diseaseassociated genes (RetNet https://sph.uth.edu/retnet/) was performed according to the previously published methods (Fujinami et al, 2016;Oishi et al, 2016;Pontikos et al, 2020;Yang et al, 2020). The identified variants were filtered using allele frequency (less than 1%) in the Human Genetic Variation Database (HGVD; http://www.hgvd.…”

RP2‐associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review, identifying a genotype–phenotype association

“…Patients with a clinical diagnosis of IRD and available whole‐exome sequencing (WES) genetic data were studied between 2008 and 2018. A total of 1,294 subjects from 730 families for whom genotype–phenotype association studies were completed, were surveyed, including 47 families with XLRP and 141 families with sporadic RP (Fujinami et al, 2016; Fujinami et al, 2019; Fujinami‐Yokokawa et al, 2019; Fujinami‐Yokokawa et al, 2020; Kameya et al, 2019; Katagiri et al, 2020; Kondo et al, 2019; Maeda‐Katahira et al, 2019; Mawatari et al, 2019; Mizobuchi et al, 2019; Nakamura et al, 2019; Nakanishi et al, 2016; Pontikos et al, 2020; Xiao Liu et al, 2020; Yang et al, 2020).…”

Prediction of causative genes in inherited retinal disorder from fundus photography and autofluorescence imaging using deep learning techniques

“… 2 The provision of accurate diagnosis of IRD is still difficult or unavailable in most of the world due to the limited access to multidisciplinary teams of specialists who can perform specific clinical investigations, including retinal imaging as well as genetic testing, interpretation of genetic results (ie, genetic diagnosis), and counselling. 4 There are currently few approved treatment approaches for IRD. 5 6 Thus, it is widely recognised that the development of accurate gene-specific diagnosis and novel therapeutic interventions is crucial to meet the urgent unmet needs of people suffering from blindness due to IRD.…”