A toolkit for genetics providers in follow‐up of patients with non‐diagnostic exome sequencing. Issue 2 (9th April 2019)

• Record Type: Journal Article
• Authors: Zastrow, Diane B.; Kohler, Jennefer N.; Bonner, Devon; Reuter, Chloe M.; Fernandez, Liliana; Grove, Megan E.; Fisk, Dianna G.; Yang, Yaping; Eng, Christine M.; Ward, Patricia A.; Bick, David; Worthey, Elizabeth A.; Fisher, Paul G.; Ashley, Euan A.; Bernstein, Jonathan A.; Wheeler, Matthew T.
• Other Names: Merker Jason investigator.; Schelley Susan investigator.; Enns Gregory investigator.; Montgomery Stephen investigator.; Zappala Zach investigator.; Fresard Laure investigator.; Prybol Cameron investigator.; Taylor Robert investigator.; McFarland Robert investigator.; Holmes Matthew investigator.; Thompson Kyle investigator.; Olahova Monika investigator.; Adams David R. investigator.; Aday Aaron investigator.; Alejandro Mercedes E. investigator.; Allard Patrick investigator.; Azamian Mahshid S. investigator.; Bacino Carlos A. investigator.; Baker Eva investigator.; Balasubramanyam Ashok investigator.; Barseghyan Hayk investigator.; Batzli Gabriel F. investigator.; Beggs Alan H. investigator.; Behnam Babak investigator.; Bellen Hugo J. investigator.; Bican Anna investigator.; Bick David P. investigator.; Birch Camille L. investigator.; Boone Braden E. investigator.; Bostwick Bret L. investigator.; Briere Lauren C. investigator.; Brokamp Elly investigator.; Brown Donna M. investigator.; Brush Matthew investigator.; Burke Elizabeth A. investigator.; Burrage Lindsay C. investigator.; Butte Manish J. investigator.; Chen Shan investigator.; Clark Gary D. investigator.; Coakley Terra R. investigator.; Cogan Joy D. investigator.; Colley Heather A. investigator.; Cooper Cynthia M. investigator.; Cope Heidi investigator.; Craigen William J. investigator.; D'Souza Precilla investigator.; Davids Mariska investigator.; Dayal Jyoti G. investigator.; Dell'Angelica Esteban C. investigator.; Dhar Shweta U. investigator.; Dipple Katrina M. investigator.; Donnell‐Fink Laurel A. investigator.; Dorrani Naghmeh investigator.; Dorset Daniel C. investigator.; Douine Emilie D. investigator.; Draper David D. investigator.; Dries Annika M. investigator.; Eckstein David J. investigator.; Emrick Lisa T. investigator.; Enns Gregory M. investigator.; Eskin Ascia investigator.; Esteves Cecilia investigator.; Estwick Tyra investigator.; Fairbrother Laura investigator.; Ferreira Carlos investigator.; Fieg Elizabeth L. investigator.; Fogel Brent L. investigator.; Gahl William A. investigator.; Glanton Emily investigator.; Godfrey Rena A. investigator.; Goldman Alica M. investigator.; Goldstein David B. investigator.; Gould Sarah E. investigator.; Gourdine Jean‐Philippe F. investigator.; Groden Catherine A. investigator.; Gropman Andrea L. investigator.; Haendel Melissa investigator.; Hamid Rizwan investigator.; Hanchard Neil A. investigator.; High Francis investigator.; Holm Ingrid A. investigator.; Hom Jason investigator.; Howerton Ellen M. investigator.; Huang Yong investigator.; Jamal Fariha investigator.; Jiang Yong‐hui investigator.; Johnston Jean M. investigator.; Jones Angela L. investigator.; Karaviti Lefkothea investigator.; Koeller David M. investigator.; Kohane Isaac S. investigator.; Krasnewich Donna M. investigator.; Korrick Susan investigator.; Koziura Mary investigator.; Krier Joel B. investigator.; Kyle Jennifer E. investigator.; Lalani Seema R. investigator.; Lau C. Christopher investigator.; Lazar Jozef investigator.; LeBlanc Kimberly investigator.; Lee Brendan H. investigator.; Lee Hane investigator.; Levy Shawn E. investigator.; Lewis Richard A. investigator.; Lincoln Sharyn A. investigator.; Loo Sandra K. investigator.; Loscalzo Joseph investigator.; Maas Richard L. investigator.; Macnamara Ellen F. investigator.; MacRae Calum A. investigator.; Maduro Valerie V. investigator.; Majcherska Marta M. investigator.; Malicdan May Christine V. investigator.; Mamounas Laura A. investigator.; Manolio Teri A. investigator.; Markello Thomas C. investigator.; Marom Ronit investigator.; Martin Martin G. investigator.; Martínez‐Agosto Julian A. investigator.; Marwaha Shruti investigator.; May Thomas investigator.; McConkie‐Rosell Allyn investigator.; McCormack Colleen E. investigator.; McCray Alexa T. investigator.; Merker Jason D. investigator.; Metz Thomas O. investigator.; Might Matthew investigator.; Moretti Paolo M. investigator.; Morimoto Marie investigator.; Mulvihill John J. investigator.; Murdock David R. investigator.; Murphy Jennifer L. investigator.; Muzny Donna M. investigator.; Nehrebecky Michele E. investigator.; Nelson Stan F. investigator.; Newberry J. Scott investigator.; Newman John H. investigator.; Nicholas Sarah K. investigator.; Novacic Donna investigator.; Orange Jordan S. investigator.; Orengo James P. investigator.; Pallais J. Carl investigator.; Palmer Christina G. S. investigator.; Papp Jeanette C. investigator.; Parker Neil H. investigator.; Pena Loren DM. investigator.; Phillips John A. investigator.; Posey Jennifer E. investigator.; Postlethwait John H. investigator.; Potocki Lorraine investigator.; Pusey Barbara N. investigator.; Rives Lynette investigator.; Robertson Amy K. investigator.; Rodan Lance H. investigator.; Rosenfeld Jill A. investigator.; Sampson Jacinda B. investigator.; Samson Susan L. investigator.; Schoch Kelly investigator.; Scott Daryl A. investigator.; Shakachite Lisa investigator.; Sharma Prashant investigator.; Shashi Vandana investigator.; Signer Rebecca investigator.; Silverman Edwin K. investigator.; Sinsheimer Janet S. investigator.; Smith Kevin S. investigator.; Spillmann Rebecca C. investigator.; Stoler Joan M. investigator.; Stong Nicholas investigator.; Sullivan Jennifer A. investigator.; Sweetser David A. investigator.; Tan Queenie K.‐G. investigator.; Tifft Cynthia J. investigator.; Toro Camilo investigator.; Tran Alyssa A. investigator.; Urv Tiina K. investigator.; Vilain Eric investigator.; Vogel Tiphanie P. investigator.; Waggott Daryl M. investigator.; Wahl Colleen E. investigator.; Walley Nicole M. investigator.; Walsh Chris A. investigator.; Walker Melissa investigator.; Wan Jijun investigator.; Wangler Michael F. investigator.; Waters Katrina M. investigator.; Webb‐Robertson Bobbie‐Jo M. investigator.; Westerfield Monte investigator.; Wise Anastasia L. investigator.; Wolfe Lynne A. investigator.; Yamamoto Shinya investigator.; Yang John investigator.; Yoon Amanda J. investigator.; Yu Guoyun investigator.; Zhao Chunli investigator.; Zheng Allison investigator.;
• Is Part Of: Journal of genetic counseling. Volume 28:Issue 2(2019)
• Page Start: 213
• Page End: 228
• Publication Date: 2019-04-09
• Subjects: exome sequencing -- genome sequencing -- rare diseases -- sequencing reanalysis -- undiagnosed diseases; Genetic counseling -- Periodicals; 616.042
• DOI: 10.1002/jgc4.1119
• Languages: English
• ISSNs: 1059-7700

Abstract

Abstract: There are approximately 7, 000 rare diseases affecting 25–30 million Americans, with 80% estimated to have a genetic basis. This presents a challenge for genetics practitioners to determine appropriate testing, make accurate diagnoses, and conduct up‐to‐date patient management. Exome sequencing (ES) is a comprehensive diagnostic approach, but only 25%–41% of the patients receive a molecular diagnosis. The remaining three‐fifths to three‐quarters of patients undergoing ES remain undiagnosed. The Stanford Center for Undiagnosed Diseases (CUD), a clinical site of the Undiagnosed Diseases Network, evaluates patients with undiagnosed and rare diseases using a combination of methods including ES. Frequently these patients have non‐diagnostic ES results, but strategic follow‐up techniques identify diagnoses in a subset. We present techniques used at the CUD that can be adopted by genetics providers in clinical follow‐up of cases where ES is non‐diagnostic. Solved case examples illustrate different types of non‐diagnostic results and the additional techniques that led to a diagnosis. Frequent approaches include segregation analysis, data reanalysis, genome sequencing, additional variant identification, careful phenotype‐disease correlation, confirmatory testing, and case matching. We also discuss prioritization of cases for additional analyses.