Inferring compound heterozygosity from large-scale exome sequencing data

Michael H. Guo, Laurent C. Francioli, Sarah L. Stenton, Julia K. Goodrich, Nicholas A. Watts, Moriel Singer-Berk, Emily Groopman, Philip W. Darnowsky, Matthew Solomonson, Samantha Baxter, Maria Abreu, Carlos A.Aguilar Salinas, Tariq Ahmad, Christine M. Albert, Jessica Alföldi, Diego Ardissino, Irina M. Armean, Gil Atzmon, Eric Banks, John BarnardSamantha M. Baxter, Laurent Beaugerie, Emelia J. Benjamin, David Benjamin, Louis Bergelson, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Bottinger, Donald W. Bowden, Matthew J. Bown, Steven Brant, Sarah E. Calvo, Hannia Campos, John C. Chambers, Juliana C. Chan, Katherine R. Chao, Sinéad Chapman, Daniel Chasman, Siwei Chen, Rex L. Chisholm, Judy Cho, Rajiv Chowdhury, Mina K. Chung, Wendy K. Chung, Kristian Cibulskis, Bruce Cohen, Ryan L. Collins, Kristen M. Connolly, Adolfo Correa, Miguel Covarrubias, Beryl Cummings, Dana Dabelea, John Danesh, Dawood Darbar, Joshua Denny, Stacey Donnelly, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosua, James Emery, Eleina England, Jeanette Erdmann, Tõnu Esko, Emily Evangelista, Yossi Farjoun, Diane Fatkin, Steven Ferriera, Jose Florez, Andre Franke, Martti Färkkilä, Stacey Gabriel, Kiran Garimella, Laura D. Gauthier, Jeff Gentry, Gad Getz, David C. Glahn, Benjamin Glaser, Stephen J. Glatt, David Goldstein, Clicerio Gonzalez, Leif Groop, Sanna Gudmundsson, Namrata Gupta, Andrea Haessly, Christopher Haiman, Ira Hall, Craig Hanis, Matthew Harms, Mikko Hiltunen, Matti M. Holi, Christina M. Hultman, Chaim Jalas, Thibault Jeandet, Mikko Kallela, Diane Kaplan, Jaakko Kaprio, Sekar Kathiresan, Eimear Kenny, Bong Jo Kim, Young Jin Kim, George Kirov, Zan Koenig, Jaspal Kooner, Seppo Koskinen, Harlan M. Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Nicole Lake, Trevyn Langsford, Kristen M. Laricchia, Terho Lehtimäki, Monkol Lek, Emily Lipscomb, Christopher Llanwarne, Ruth J.F. Loos, Steven A. Lubitz, Teresa Tusie Luna, Ronald C.W. Ma, Gregory M. Marcus, Jaume Marrugat, Alicia R. Martin, Kari M. Mattila, Steven McCarroll, Mark I. McCarthy, Jacob McCauley, Dermot McGovern, Ruth McPherson, James B. Meigs, Olle Melander, Andres Metspalu, Deborah Meyers, Eric V. Minikel, Braxton D. Mitchell, Vamsi K. Mootha, Ruchi Munshi, Aliya Naheed, Saman Nazarian, Peter M. Nilsson, Sam Novod, Anne H. O’Donnell-Luria, Michael C. O’Donovan, Yukinori Okada, Dost Ongur, Lorena Orozco, Michael J. Owen, Colin Palmer, Nicholette D. Palmer, Aarno Palotie, Kyong Soo Park, Carlos Pato, Nikelle Petrillo, William Phu, Timothy Poterba, Ann E. Pulver, Dan Rader, Nazneen Rahman, Alex Reiner, Anne M. Remes, Dan Rhodes, Stephen Rich, John D. Rioux, Samuli Ripatti, David Roazen, Dan M. Roden, Jerome I. Rotter, Valentin Ruano-Rubio, Nareh Sahakian, Danish Saleheen, Veikko Salomaa, Andrea Saltzman, Nilesh J. Samani, Jeremiah Scharf, Molly Schleicher, Heribert Schunkert, Sebastian Schönherr, Eleanor Seaby, Cotton Seed, Svati H. Shah, Megan Shand, Moore B. Shoemaker, Tai Shyong, Edwin K. Silverman, Pamela Sklar, J. Gustav Smith, Jonathan T. Smith, Hilkka Soininen, Harry Sokol, Rachel G. Son, Jose Soto, Tim Spector, Christine Stevens, Nathan Stitziel, Patrick F. Sullivan, Jaana Suvisaari, E. Shyong Tai, Michael E. Talkowski, Yekaterina Tarasova, Kent D. Taylor, Yik Ying Teo, Kathleen Tibbetts, Charlotte Tolonen, Ming Tsuang, Tiinamaija Tuomi, Dan Turner, Teresa Tusie-Luna, Erkki Vartiainen, Marquis Vawter, Christopher Vittal, Gordon Wade, Arcturus Wang, Qingbo Wang, James S. Ware, Hugh Watkins, Rinse K. Weersma, Ben Weisburd, Maija Wessman, Nicola Whiffin, Michael W. Wilson, James G. Wilson, Ramnik J. Xavier, Mary T. Yohannes, Grace Tiao, Benjamin M. Neale, Joel N. Hirschhorn, Heidi L. Rehm, Mark J. Daly, Anne O’Donnell-Luria, Konrad J. Karczewski, Daniel G. MacArthur, Kaitlin E. Samocha

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. Here we developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in the Genome Aggregation Database (v2, n = 125,748 exomes). Our approach estimates phase with 96% accuracy, both in trio data and in patients with Mendelian conditions and presumed causal compound heterozygous variants. We provide a public resource of phasing estimates for coding variants and counts per gene of rare variants in trans that can aid interpretation of rare co-occurring variants in the context of recessive disease.

Original languageEnglish (US)
Pages (from-to)152-161
Number of pages10
JournalNature Genetics
Volume56
Issue number1
DOIs
StatePublished - Jan 2024

ASJC Scopus subject areas

  • Genetics

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