Phen2Gene: Rapid Phenotype-driven Gene Prioritization for Rare Diseases

Overview

Journal NAR Genom Bioinform

Publisher Oxford University Press

Specialty Biology

Date 2020 Jun 6

PMID 32500119

Citations 44

Authors

Mengge Zhao

James M Havrilla

Li Fang

Ying Chen

Jacqueline Peng

Cong Liu

Chao Wu

Mahdi Sarmady

Pablo Botas

Julian Isla

Gholson J Lyon

Chunhua Weng

Kai Wang

Affiliations

Soon will be listed here.

Abstract

Human Phenotype Ontology (HPO) terms are increasingly used in diagnostic settings to aid in the characterization of patient phenotypes. The HPO annotation database is updated frequently and can provide detailed phenotype knowledge on various human diseases, and many HPO terms are now mapped to candidate causal genes with binary relationships. To further improve the genetic diagnosis of rare diseases, we incorporated these HPO annotations, gene-disease databases and gene-gene databases in a probabilistic model to build a novel HPO-driven gene prioritization tool, Phen2Gene. Phen2Gene accesses a database built upon this information called the HPO2Gene Knowledgebase (H2GKB), which provides weighted and ranked gene lists for every HPO term. Phen2Gene is then able to access the H2GKB for patient-specific lists of HPO terms or PhenoPacket descriptions supported by GA4GH (http://phenopackets.org/), calculate a prioritized gene list based on a probabilistic model and output gene-disease relationships with great accuracy. Phen2Gene outperforms existing gene prioritization tools in speed and acts as a real-time phenotype-driven gene prioritization tool to aid the clinical diagnosis of rare undiagnosed diseases. In addition to a command line tool released under the MIT license (https://github.com/WGLab/Phen2Gene), we also developed a web server and web service (https://phen2gene.wglab.org/) for running the tool via web interface or RESTful API queries. Finally, we have curated a large amount of benchmarking data for phenotype-to-gene tools involving 197 patients across 76 scientific articles and 85 patients' de-identified HPO term data from the Children's Hospital of Philadelphia.

Citing Articles

A clinical knowledge graph-based framework to prioritize candidate genes for facilitating diagnosis of Mendelian diseases and rare genetic conditions.

Gnanaolivu R, Oliver G, Jenkinson G, Blake E, Chen W, Chia N BMC Bioinformatics. 2025; 26(1):82.

PMID: 40087567 DOI: 10.1186/s12859-025-06096-2.

A phenotype-based AI pipeline outperforms human experts in differentially diagnosing rare diseases using EHRs.

Mao X, Huang Y, Jin Y, Wang L, Chen X, Liu H NPJ Digit Med. 2025; 8(1):68.

PMID: 39875532 PMC: 11775211. DOI: 10.1038/s41746-025-01452-1.

Phenotype driven molecular genetic test recommendation for diagnosing pediatric rare disorders.

Chen F, Ahimaz P, Nguyen Q, Lewis R, Chung W, Ta C NPJ Digit Med. 2024; 7(1):333.

PMID: 39572625 PMC: 11582592. DOI: 10.1038/s41746-024-01331-1.

Implications of mappings between International Classification of Diseases clinical diagnosis codes and Human Phenotype Ontology terms.

Tan A, Goncalves R, Yuan W, Brat G, Gentleman R, Kohane I JAMIA Open. 2024; 7(4):ooae118.

PMID: 39559493 PMC: 11570992. DOI: 10.1093/jamiaopen/ooae118.

A corpus of GA4GH phenopackets: Case-level phenotyping for genomic diagnostics and discovery.

Danis D, Bamshad M, Bridges Y, Caballero-Oteyza A, Cacheiro P, Carmody L HGG Adv. 2024; 6(1):100371.

PMID: 39394689 PMC: 11564936. DOI: 10.1016/j.xhgg.2024.100371.

References

De Mori R, Romani M, DArrigo S, Zaki M, Lorefice E, Tardivo S . Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects. Am J Hum Genet. 2017; 101(4):552-563. PMC: 5630196. DOI: 10.1016/j.ajhg.2017.08.017. View

Inlora J, Sailani M, Khodadadi H, Teymurinezhad A, Takahashi S, Bernstein J . Identification of a novel mutation in the gene associated with ataxia-oculomotor apraxia. Cold Spring Harb Mol Case Stud. 2017; 3(6). PMC: 5701303. DOI: 10.1101/mcs.a002014. View

Haskell G, Mori M, Powell C, Amrhein T, Rice G, Bailey L . Combination of exome sequencing and immune testing confirms Aicardi-Goutières syndrome type 5 in a challenging pediatric neurology case. Cold Spring Harb Mol Case Stud. 2018; 4(5). PMC: 6169830. DOI: 10.1101/mcs.a002758. View

Joshi M, Anselm I, Shi J, Bale T, Towne M, Schmitz-Abe K . Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease. Cold Spring Harb Mol Case Stud. 2016; 2(3):a000786. PMC: 4853520. DOI: 10.1101/mcs.a000786. View

Caglayan A, Sezer R, Kaymakcalan H, Ulgen E, Yavuz T, Baranoski J . gene mutation in a patient with congenital cardiomyopathy and dysmorphic features. Cold Spring Harb Mol Case Stud. 2017; 3(5). PMC: 5593152. DOI: 10.1101/mcs.a001859. View

Bayram Y, White J, Elcioglu N, Cho M, Zadeh N, Gedikbasi A . REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis. Am J Hum Genet. 2017; 101(1):149-156. PMC: 5501868. DOI: 10.1016/j.ajhg.2017.06.006. View

Son J, Xie G, Yuan C, Ena L, Li Z, Goldstein A . Deep Phenotyping on Electronic Health Records Facilitates Genetic Diagnosis by Clinical Exomes. Am J Hum Genet. 2018; 103(1):58-73. PMC: 6035281. DOI: 10.1016/j.ajhg.2018.05.010. View

McKusick V . Mendelian Inheritance in Man and its online version, OMIM. Am J Hum Genet. 2007; 80(4):588-604. PMC: 1852721. DOI: 10.1086/514346. View

Polfus L, Boerwinkle E, Gibbs R, Metcalf G, Muzny D, Veeraraghavan N . Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome. Cold Spring Harb Mol Case Stud. 2016; 2(6):a001255. PMC: 5111009. DOI: 10.1101/mcs.a001255. View

10.

Windpassinger C, Piard J, Bonnard C, Alfadhel M, Lim S, Bisteau X . CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. Am J Hum Genet. 2017; 101(3):391-403. PMC: 5591019. DOI: 10.1016/j.ajhg.2017.08.003. View

11.

Berland S, Toft-Bertelsen T, Aukrust I, Byska J, Vaudel M, Bindoff L . A de novo Ser111Thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance. Cold Spring Harb Mol Case Stud. 2018; 4(1). PMC: 5793774. DOI: 10.1101/mcs.a002303. View

12.

Lu J, Bishop J, Cheyette S, Zhulin I, Guo S, Sobreira N . A novel pathogenic variant in a family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures. Cold Spring Harb Mol Case Stud. 2017; 4(1). PMC: 5793775. DOI: 10.1101/mcs.a002287. View

13.

Murry J, Machini K, Ceyhan-Birsoy O, Kritzer A, Krier J, Lebo M . Reconciling newborn screening and a novel splice variant in associated with partial biotinidase deficiency: a BabySeq Project case report. Cold Spring Harb Mol Case Stud. 2018; 4(4). PMC: 6071571. DOI: 10.1101/mcs.a002873. View

14.

Boudin E, de Jong T, Prickett T, Lapauw B, Toye K, Van Hoof V . Bi-allelic Loss-of-Function Mutations in the NPR-C Receptor Result in Enhanced Growth and Connective Tissue Abnormalities. Am J Hum Genet. 2018; 103(2):288-295. PMC: 6080727. DOI: 10.1016/j.ajhg.2018.06.007. View

15.

Webster E, Cho M, Alexander N, Desai S, Naidu S, Bekheirnia M . De novo -predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features. Cold Spring Harb Mol Case Stud. 2016; 2(6):a001172. PMC: 5111011. DOI: 10.1101/mcs.a001172. View

16.

Delpire E, Wolfe L, Flores B, Koumangoye R, Schornak C, Omer S . A patient with multisystem dysfunction carries a truncation mutation in human , the gene encoding the Na-K-2Cl cotransporter, NKCC1. Cold Spring Harb Mol Case Stud. 2016; 2(6):a001289. PMC: 5111002. DOI: 10.1101/mcs.a001289. View

17.

Griffin L, Farley F, Antonellis A, Keegan C . A novel FGD1 mutation in a family with Aarskog-Scott syndrome and predominant features of congenital joint contractures. Cold Spring Harb Mol Case Stud. 2016; 2(4):a000943. PMC: 4990810. DOI: 10.1101/mcs.a000943. View

18.

Malcolmson J, Kleyner R, Tegay D, Adams W, Ward K, Coppinger J . mutation in a child presenting with seizures and developmental delays. Cold Spring Harb Mol Case Stud. 2016; 2(6):a001073. PMC: 5111007. DOI: 10.1101/mcs.a001073. View

19.

Chapman W, Bridewell W, Hanbury P, Cooper G, Buchanan B . A simple algorithm for identifying negated findings and diseases in discharge summaries. J Biomed Inform. 2002; 34(5):301-10. DOI: 10.1006/jbin.2001.1029. View

20.

Stelzer G, Plaschkes I, Oz-Levi D, Alkelai A, Olender T, Zimmerman S . VarElect: the phenotype-based variation prioritizer of the GeneCards Suite. BMC Genomics. 2016; 17 Suppl 2:444. PMC: 4928145. DOI: 10.1186/s12864-016-2722-2. View