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NPJ Genom Med. 2018 Aug 13;3:21. doi: 10.1038/s41525-018-0060-9. eCollection 2018.

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Author information

1
1Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.
2
2Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.
3
3Department of Genetics, Harvard Medical School, Boston, MA 02115 USA.
4
4Howard Hughes Medical Institute, Brigham and Womens Hospital, Boston, MA 02115 USA.
5
5Broad Institute of Harvard and MIT, Cambridge, MA 02142 USA.
6
6Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
7
7Division of Genetics and Genomics, Department of Medicine, Boston Childrens Hospital, Harvard Medical School, Boston, MA 02115 USA.
8
8Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Boston Childrens Hospital, Harvard Medical School, Boston, MA 02115 USA.
9
9Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02115 USA.
10
10Dana-Farber Cancer Institute, Boston, MA 02115 USA.
11
11Cardiovascular Division, Department of Medicine; Department of Genetics; McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO 63110 USA.
12
12Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02215 USA.
13
13Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Harvard Medical School, Boston, MA 02114 USA.
14
14Division of Plastic and Reconstructive Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
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15Feingold Center for Children, Childrens Hospital Boston at Waltham, Waltham, MA 02453 USA.
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16Department of Pediatrics, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048 USA.
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17Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143 USA.
18
18Department of Neurology, Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02115 USA.
19
19Division of Rheumatology, Allergy and Immunology, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA 02115 USA.
20
20Institute of Inflammation and Repair, University of Manchester, Manchester, UK.

Abstract

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs.

Conflict of interest statement

R.C.G. receives compensation for speaking or advisory services from AIA, Genome Medical, Helix, Invitae, Illumina, Prudential, and Roche. R.C.G., N.F., and S.R.S. are on the board of Veritas Genetics. C.A.M. receives compensation for advisory services from Personome and Recombine, and royalties for genetic testing from Partners HealthCare. The other authors declare no competing interests.

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