Phenogenon: Gene to phenotype associations for rare genetic diseases

Nikolas Pontikos; Cian Murphy; Ismail Moghul; Gavin Arno; Kaoru Fujinami; Yu Fujinami; Dayyanah Sumodhee; Susan Downes; Andrew Webster; Jing Yu; UK Inherited Retinal Dystrophy Consortium, Phenopolis Consortium

doi:10.1371/journal.pone.0230587

Phenogenon: Gene to phenotype associations for rare genetic diseases

PLoS One. 2020 Apr 9;15(4):e0230587. doi: 10.1371/journal.pone.0230587. eCollection 2020.

Authors

Nikolas Pontikos^{1

2

3}, Cian Murphy^{1

4}, Ismail Moghul⁵, Gavin Arno^{2

3

6}, Kaoru Fujinami^{2

3

6

7}, Yu Fujinami^{8

9}, Dayyanah Sumodhee¹⁰, Susan Downes^{11

12}, Andrew Webster^{2

3}, Jing Yu¹²; UK Inherited Retinal Dystrophy Consortium, Phenopolis Consortium

Affiliations

¹ UCL Genetics Institute, University College London, London, United Kingdom.
² Institute of Ophthalmology, University College London, London, United Kingdom.
³ Moorfields Eye Hospital, London, United Kingdom.
⁴ Warwick Medical School, University of Warwick, Coventry, United Kingdom.
⁵ UCL Cancer Institute, University College London, London, United Kingdom.
⁶ Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
⁷ Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
⁸ Graduate School of Health Management, Keio University, Tokyo, Japan.
⁹ Division of Public Health, Yokokawa Clinic, Osaka, Japan.
¹⁰ Queen Mary University, Mile End Road, Bethnal Green, London, United Kingdom.
¹¹ Oxford Eye Hospital, West Wing, John Radcliffe Hospital, Oxford, United Kingdom.
¹² Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3-Oxo-5-alpha-Steroid 4-Dehydrogenase / genetics
Cohort Studies
Computational Biology / methods*
DNA-Binding Proteins / genetics
Databases, Genetic
Exome Sequencing
Gene Frequency
Genetic Association Studies* / methods
Genetic Association Studies* / statistics & numerical data
Genetic Diseases, Inborn* / epidemiology
Genetic Diseases, Inborn* / genetics
Genetic Predisposition to Disease
Genotype
High-Throughput Nucleotide Sequencing* / methods
High-Throughput Nucleotide Sequencing* / statistics & numerical data
Humans
Membrane Proteins / genetics
Monomeric GTP-Binding Proteins / genetics
Nail Diseases / epidemiology
Nail Diseases / genetics
Phenotype
Rare Diseases* / epidemiology
Rare Diseases* / genetics
Retinal Dystrophies / epidemiology
Retinal Dystrophies / genetics
Skin Diseases / epidemiology
Skin Diseases / genetics
Transcription Factors / genetics

Substances

DNA-Binding Proteins
GRHL2 protein, human
Membrane Proteins
Transcription Factors
3-Oxo-5-alpha-Steroid 4-Dehydrogenase
SRD5A3 protein, human
RRAGA protein, human
Monomeric GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding