Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care

S L Sawyer¹, T Hartley¹, D A Dyment¹, C L Beaulieu¹, J Schwartzentruber², A Smith¹, H M Bedford³, G Bernard⁴, F P Bernier⁵, B Brais⁶, D E Bulman¹, J Warman Chardon⁷, D Chitayat^{8

9}, J Deladoëy¹⁰, B A Fernandez¹¹, P Frosk¹², M T Geraghty¹, B Gerull¹³, W Gibson¹⁴, R M Gow¹⁵, G E Graham¹, J S Green¹¹, E Heon¹⁶, G Horvath¹⁷, A M Innes⁵, N Jabado¹⁸, R H Kim^{8

19}, R K Koenekoop²⁰, A Khan⁵, O J Lehmann²¹, R Mendoza-Londono⁸, J L Michaud¹⁰, S M Nikkel¹, L S Penney²², C Polychronakos¹⁸, J Richer¹, G A Rouleau²³, M E Samuels¹⁰, V M Siu²⁴, O Suchowersky²⁵, M A Tarnopolsky²⁶, G Yoon⁸, F R Zahir¹⁴; FORGE Canada Consortium; Care4Rare Canada Consortium; J Majewski¹⁸, K M Boycott¹

Affiliations

¹ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
² McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
³ Genetics Program, North York General Hospital, Toronto, Canada.
⁴ Departments of Pediatrics, Neurology and Neurosurgery, Division of Pediatric Neurology, Montréal Children's Hospital, Research Institute of the McGill University Health Centre, Montreal, Canada.
⁵ Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
⁶ Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada.
⁷ Department of Neurology, The Ottawa Hospital, Ottawa, Canada.
⁸ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
⁹ The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
¹⁰ Department of Medicine, Centre de Recherche du CHU Ste-Justine, University of Montreal, Montreal, Canada.
¹¹ Disciplines of Genetics and Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
¹² Departments of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada.
¹³ Cardiac Sciences and Medical Genetics, University of Calgary, Calgary, Canada.
¹⁴ Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
¹⁵ Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
¹⁶ Department of Ophthalmology and Vision Sciences, Program of Genetics and Genomic Biology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
¹⁷ Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada.
¹⁸ Departments of Pediatrics and Human Genetics, McGill University, Montreal, Canada.
¹⁹ Department of Medicine, University of Toronto, Toronto, Canada.
²⁰ McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Canada.
²¹ Departments of Ophthalmology and Medical Genetics, University of Alberta, Edmonton, Canada.
²² Medical Genetics, IWK Health Centre, Halifax, Canada.
²³ Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.
²⁴ Division of Medical Genetics, Department of Pediatrics, University of Western Ontario, London, Canada.
²⁵ Departments of Medicine, Medical Genetics, and Pediatrics, University of Alberta, Edmonton, Canada.
²⁶ Department of Pediatrics, McMaster University, Hamilton, Canada.

PMID: 26283276
PMCID: PMC5053223
DOI: 10.1111/cge.12654

Review

Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care

S L Sawyer et al. Clin Genet. 2016 Mar.

. 2016 Mar;89(3):275-84.

doi: 10.1111/cge.12654. Epub 2015 Sep 22.

Authors

Affiliations

¹ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
² McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
³ Genetics Program, North York General Hospital, Toronto, Canada.
⁴ Departments of Pediatrics, Neurology and Neurosurgery, Division of Pediatric Neurology, Montréal Children's Hospital, Research Institute of the McGill University Health Centre, Montreal, Canada.
⁵ Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
⁶ Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada.
⁷ Department of Neurology, The Ottawa Hospital, Ottawa, Canada.
⁸ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
⁹ The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
¹⁰ Department of Medicine, Centre de Recherche du CHU Ste-Justine, University of Montreal, Montreal, Canada.
¹¹ Disciplines of Genetics and Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
¹² Departments of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada.
¹³ Cardiac Sciences and Medical Genetics, University of Calgary, Calgary, Canada.
¹⁴ Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
¹⁵ Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
¹⁶ Department of Ophthalmology and Vision Sciences, Program of Genetics and Genomic Biology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
¹⁷ Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada.
¹⁸ Departments of Pediatrics and Human Genetics, McGill University, Montreal, Canada.
¹⁹ Department of Medicine, University of Toronto, Toronto, Canada.
²⁰ McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Canada.
²¹ Departments of Ophthalmology and Medical Genetics, University of Alberta, Edmonton, Canada.
²² Medical Genetics, IWK Health Centre, Halifax, Canada.
²³ Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.
²⁴ Division of Medical Genetics, Department of Pediatrics, University of Western Ontario, London, Canada.
²⁵ Departments of Medicine, Medical Genetics, and Pediatrics, University of Alberta, Edmonton, Canada.
²⁶ Department of Pediatrics, McMaster University, Hamilton, Canada.

PMID: 26283276
PMCID: PMC5053223
DOI: 10.1111/cge.12654

Abstract

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

Keywords: FORGE Canada Consortium; clinical exome; rare diseases; whole-exome sequencing.

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Figures

**Figure 1**
Outcomes of the 362 families studied using whole‐exome sequencing (WES) as part of the Finding Of Rare Disease GEnes (FORGE) Canada research study. Overall, 188 of the 362 (51.9%) families received a definitive molecular diagnosis, either in a gene previously known to cause a similar disease (known) or in a gene that had not been previously associated with the family's disease (novel). Of the 174 (48.1%) of families that remain unsolved, 28 have single‐surviving candidates for which we are gathering additional evidence to support pathogenicity.

See this image and copyright information in PMC

References

1. Orphanet. Prevalence of rare diseases: Bibliographic data. Orphanet Reports Series 2014; Rare Diseases collection.
1. McKusick VA. Mendelian Inheritance in Man and its online version, OMIM. Am J Hum Genet 2007: 80: 588–604. - PMC - PubMed
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Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care

Affiliations

Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical