Abstract
Precision medicine requires precise genetic variant interpretation, yet many disease-associated genes have unresolved variants of unknown significance (VUS). We analyzed variants in a well-studied gene, FGFR1, a common cause of Idiopathic Hypogonadotropic Hypogonadism (IHH) and examined whether regional genetic enrichment of missense variants could improve variant classification. FGFR1 rare sequence variants (RSVs) were examined in a large cohort to (i) define regional genetic enrichment, (ii) determine pathogenicity based on the American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) variant classification framework, and (iii) characterize the phenotype of FGFR1 variant carriers by variant classification. A total of 143 FGFR1 RSVs were identified in 175 IHH probands (n = 95 missense, n = 48 protein-truncating variants). FGFR1 missense RSVs showed regional enrichment across biologically well-defined domains: D1, D2, D3, and TK domains and linker regions (D2–D3, TM–TK). Using these defined regions of enrichment to augment the ACMG/AMP classification reclassifies 37% (20/54) of FGFR1 missense VUS as pathogenic or likely pathogenic (PLP). Non-proband carriers of FGFR1 missense VUS variants that were reclassified as PLP were more likely to express IHH or IHH-associated phenotypes [anosmia or delayed puberty] than non-proband carriers of FGFR1 missense variants that remained as VUS (76.9% vs 34.7%, p = 0.035). Using the largest cohort of FGFR1 variant carriers, we show that integration of regional genetic enrichment as moderate evidence for pathogenicity improves the classification of VUS and that reclassified variants correlated with phenotypic expressivity. The addition of regional genetic enrichment to the ACMG/AMP guidelines may improve clinical variant interpretation.
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Data Availability
Confirmed sequencing data for variants in this manuscript are deposited into ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/; submissions SCV003932463–SCV003932605). Data generated or analyzed during this study are included in this published article and its supplementary information files. Additional data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
This work was supported by the Eunice K. Shriver National Institute for Child Health and Human Development (P50 HD-28138 to S.B.S., support for W.X. and L.P., 1K23HD097296 to M.F.L., K23 HD077043 to R.B., R01 HD096324 to R.B.); Catalyst Medical Research Investigator Training Award to M.F.L.; National Center for Advancing Translational Sciences, National Institutes of Health Award UL 1TR002541 and by financial contributions from Harvard University and its affiliated academic health care centers to Harvard Catalyst/the Harvard Clinical and Translational Science Center. S.B.S. is a Robert and Laura Reynolds Research Scholar. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University, its affiliated academic health care centers, or the National Institutes of Health. We thank the research subjects and referring providers [Fotini Adamidou, Tania Aguirre, Iram Ahmad, Abdulmoein Al-Agha, Jonathan Anolik, Anita Azam, Bert Bachrach, Hagit Baris, Gerhard Baumann, Lynn Bennion, Pierre Bouloux, Jan Bruder, Jean Pierre Chanoine, Jeannette Chinchilla, Jin-Ho Choi, Thomas P Clairmont, Amy Criego, Ashwin Dalal, Angela Delaney, Rachel Edelen, Deborah Elder, Micheal Fili, Eric Fliers, John Fowlkes, Larry Fox, Peter Fuller, Dieter Furthner, Neoklis Georgopoulos, Nadine Haddad, Sheri Horsburgh, Louise Izatt, Silvia Kaufmann, Sjoberg Kho, Susan Kirsch, Peter Kopp, Mariarosaria Lang-Muritano, Helene Lavoie, Peter Lee, Selwyn B. Levitt, Irene Mamkin, Veronica Mericq, Daniel Metzger, Kiyonori Miura, Ron Newfield, Metin Ozata, Jose Perez-Rodiguez, Duarte Pignatelli, Richard Quintin, Jose Quintos, Sally Radovick, Cesar Ramos-Remus, Barry Reiner, Elise Rodman, Craig Sadur, Nicole Simon, Arnold Slyper, Rebecca Sokol, Susan Sparks, Phyllis Speiser, Dennis Styne, Diane Suchet, Akira Takeshita, Arthi Thirumalai, Sherida Tollefsen, Kemal Topalolgu, Marshall Tulloch-Reid, Guy Van Vliet, Charles Verge, Teresa Vieira, Darren West, Melissa Woo], without whom this research would not be possible. We also thank Kathy Salnikov and other members of the MGH Reproductive Endocrine Unit for their assistance and input. We thank Andrew Dwyer for reviewing the manuscript. We thank the staff of the Broad Genomic Core.
Funding
This work was supported by the Eunice K. Shriver National Institute for Child Health and Human Development (P50 HD-28138 to S.B.S., support for W.X. and L.P., 1K23HD097296 to M.F.L., K23 HD077043 to R.B., R01 HD096324 to R.B.); Catalyst Medical Research Investigator Training Award to M.F.L.; National Center for Advancing Translational Sciences, National Institutes of Health Award UL 1TR002541 and by financial contributions from Harvard University and its affiliated academic health care centers to Harvard Catalyst/the Harvard Clinical and Translational Science Center. S.B.S. is a Robert and Laura Reynolds Research Scholar. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University, its affiliated academic health care centers, or the National Institutes of Health.
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WX and MFL contributed to the study conception and design. Material preparation, data collection and analysis were performed by WX, MFL, LP. Data interpretation was performed by WX, MFL, RB, SBS. The first draft of the manuscript was written by WX and MFL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Xu, W., Plummer, L., Seminara, S.B. et al. How human genetic context can inform pathogenicity classification: FGFR1 variation in idiopathic hypogonadotropic hypogonadism. Hum. Genet. 142, 1611–1619 (2023). https://doi.org/10.1007/s00439-023-02601-w
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DOI: https://doi.org/10.1007/s00439-023-02601-w