GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

Roozbeh Manshaei; Sean DeLong; Veronica Andric; Esha Joshi; John B A Okello; Priya Dhir; Cherith Somerville; Kirsten M Farncombe; Kelsey Kalbfleisch; Rebekah K Jobling; Stephen W Scherer; Raymond H Kim; S Mohsen Hosseini

doi:10.1186/s12920-022-01166-3

GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

BMC Med Genomics. 2022 Feb 18;15(1):31. doi: 10.1186/s12920-022-01166-3.

Authors

Roozbeh Manshaei¹, Sean DeLong^{1

2}, Veronica Andric^#¹, Esha Joshi^#^{1

3}, John B A Okello^{1

4}, Priya Dhir^{1

5}, Cherith Somerville¹, Kirsten M Farncombe⁶, Kelsey Kalbfleisch^{1

7}, Rebekah K Jobling^{1

8

7}, Stephen W Scherer^{9

10

11

12}, Raymond H Kim^{13

14}, S Mohsen Hosseini¹⁵

Affiliations

¹ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
² Department of Electrical Engineering and Computer Science, York University, Toronto, ON, Canada.
³ Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁴ MIT Sloan School of Management, Massachusetts Institute of Technology, 100 Main Street, Cambridge, MA, 02142, USA.
⁵ Faculty of Medicine, University of Toronto, Toronto, ON, M5S1A8, Canada.
⁶ Ted Rogers Centre for Heart Research, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
⁷ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
⁸ Genome Diagnostics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁰ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
¹² Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹³ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. raymond.kim@sickkids.ca.
¹⁴ Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Department of Medicine, University of Toronto, Toronto, ON, Canada. raymond.kim@sickkids.ca.
¹⁵ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. smhosseini@mdanderson.org.

^# Contributed equally.

Abstract

Background: Variant interpretation is the main bottleneck in medical genomic sequencing efforts. This usually involves genome analysts manually searching through a multitude of independent databases, often with the aid of several, mostly independent, computational tools. To streamline variant interpretation, we developed the GeneTerpret platform which collates data from current interpretation tools and databases, and applies a phenotype-driven query to categorize the variants identified in the genome(s). The platform assigns quantitative validity scores to genes by query and assembly of the genotype-phenotype data, sequence homology, molecular interactions, expression data, and animal models. It also uses the American College of Medical Genetics and Genomics (ACMG) criteria to categorize variants into five tiers of pathogenicity. The final output is a prioritized list of potentially causal variants/genes.

Results: We tested GeneTerpret by comparing its performance to expert-curated genes (ClinGen's gene-validity database) and variant pathogenicity reports (DECIPHER database). Output from GeneTerpret was 97.2% and 83.5% concordant with the expert-curated sources, respectively. Additionally, similar concordance was observed when GeneTerpret's performance was compared with our internal expert-interpreted clinical datasets.

Conclusions: GeneTerpret is a flexible platform designed to streamline the genome interpretation process, through a unique interface, with improved ease, speed and accuracy. This modular and customizable system allows the user to tailor the component-programs in the analysis process to their preference. GeneTerpret is available online at https://geneterpret.com .

Keywords: Bioinformatic application; Causative variants; Disease gene validity; Gene prioritization; Genome interpretation; Genomic variants; Genotype–phenotype correlation; Variant pathogenicity.

Publication types

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

MeSH terms

Genetic Variation
Genome, Human
Genomics*
Humans
Phenotype
Software*
United States

Grants and funding

WT_/Wellcome Trust/United Kingdom