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Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases

2017; Elsevier BV; Volume: 20; Issue: 4 Linguagem: Inglês

10.1038/gim.2017.128

1530-0366

Loren D.M. Peña, Yong‐Hui Jiang, Kelly Schoch, Rebecca C. Spillmann, Sophie Nicole, Nicholas Stong, Sarah R. Horn, Jennifer A. Sullivan, Allyn McConkie‐Rosell, Sujay Kansagra, Edward C. Smith, Mays El-Dairi, Jane S. Bellet, Martha Ann Keels, Joan Jasien, Peter G. Kranz, Richard J. Noel, Shashi Nagaraj, Robert K. Lark, Daniel S. Wechsler, Daniela del Gaudio, Marco L. Leung, Laura G. Hendon, Collette C. Parker, Kelly L. Jones, David B. Goldstein, Vandana Shashi, Mercedes E. Alejandro, Carlos A. Bacino, Ashok Balasubramanyam, Bret L. Bostwick, Lindsay C. Burrage, Shan Chen, Gary Clark, William J. Craigen, Shweta U. Dhar, Lisa Emrick, Brett H. Graham, Neil A. Hanchard, Mahim Jain, Seema R. Lalani, Brendan Lee, Richard A. Lewis, Mahshid S. Azamian, Paolo Moretti, Sarah K. Nicholas, Jordan S. Orange, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Jing Zhang, Hugo J. Bellen, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Donna M. Muzny, Patricia A. Ward, Yaping Yang, David B. Goldstein, Nicholas Stong, Yong‐hui Jiang, Allyn McConkie‐Rosell, Loren D.M. Peña, Kelly Schoch, Vandana Shashi, Rebecca C. Spillmann, Jennifer A. Sullivan, Sophie Nicole, Alan H. Beggs, Lauren C. Briere, Cynthia M. Cooper, Laurel A. Donnell‐Fink, Elizabeth L. Krieg, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Chris A. Walsh, Cecilia Esteves, Ingrid A. Holm, Isaac S. Kohane, Paul Mazur, Alexa T. McCray, Matthew Might, Rachel Ramoni, Kimberly Splinter, David Bick, Camille L. Birch, Braden Boone, Donna M. Brown, Daniel C. Dorset, Lori H. Handley, Howard J. Jacob, Angela Jones, Jozef Lazar, Shawn Levy, J. Scott Newberry, Molly C. Schroeder, Kimberly A. Strong, Elizabeth A. Worthey, Jyoti G. Dayal, David J. Eckstein, Sarah E. Gould, Ellen M. Howerton, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Tiina K. Urv, Anastasia L. Wise, Ariane Soldatos, Matthew Brush, Jean-Philippe F. Gourdine, Melissa Haendel, David M. Koeller, Jennifer Kyle, Thomas Metz, Katrina M. Waters, Bobbie‐Jo Webb‐Robertson, Euan A. Ashley, Jonathan A. Bernstein, Annika M. Dries, Paul G. Fisher, Jennefer N. Kohler, Daryl Waggott, Matthew T. Wheeler, Patricia A. Zornio, Patrick Allard, Hayk Barseghyan, Esteban C. Dell’Angelica, Ani Dillon, Katrina M. Dipple, Naghmeh Dorrani, Emilie D. Douine, Ascia Eskin, Brent L. Fogel, Matthew Herzog, Hane Lee, Allen Lipson, Sandra K. Loo, Julián A. Martínez-Agosto, Stan F. Nelson, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Janet S. Sinsheimer, Éric Vilain, Allison Zheng, David R. Adams, Elizabeth A. Burke, Katherine R. Chao, Mariska Davids, David D. Draper, Tyra Estwick, Trevor S. Frisby, Kate Frost, Valerie Gartner, Rena A. Godfrey, Mitchell Goheen, Gretchen Golas, Mary Grace Gordon, Catherine Groden, Mary E. Hackbarth, Isabel Hardee, Jean M. Johnston, Alanna E. Koehler, Lea Latham, Yvonne L. Latour, C. Christopher Lau, Denise J. Levy, Adam Liebendorfer, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Alexandra J. McCarty, Jennifer L. Murphy, Michele Nehrebecky, Donna Novacic, Barbara N. Pusey, Sarah Sadozai, Katherine E. Schaffer, Prashant Sharma, Sara Thomas, Nathanial J. Tolman, Camilo Toro, Zaheer Valivullah, Colleen E. Wahl, Mike Warburton, Alec A. Weech, Guoyun Yu, Andrea Gropman, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, Paul R. Lee, John H. Postlethwait, Monte Westerfield, Anna Bican, Joy D. Cogan, Rizwan Hamid, John H. Newman, John A. Phillips, Amy K. Robertson,

CRISPR and Genetic Engineering

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.