T B Balci1, T Hartley2, Y Xi2,3, D A Dyment1,2, C L Beaulieu2, F P Bernier3, L Dupuis4, G A Horvath5, R Mendoza-Londono4, C Prasad6, J Richer1, X-R Yang3, C M Armour1, E Bareke7, B A Fernandez8, H J McMillan2, R E Lamont3, J Majewski7, J S Parboosingh3, A N Prasad6, C A Rupar6, J Schwartzentruber7, A C Smith2, M Tétreault7, A M Innes3, K M Boycott1,2. 1. Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada. 2. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada. 3. Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 4. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada. 5. Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada. 6. London Health Sciences Centre, Western University, London, Ontario, Canada. 7. Department of Human Genetics, McGill University, Montréal, Québec, Canada. 8. Disciplines of Genetics and Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
Abstract
BACKGROUND: Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown. AIMS: We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada. MATERIALS & METHODS: We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. RESULTS: Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family. CONCLUSION: Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.
BACKGROUND: Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown. AIMS: We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada. MATERIALS & METHODS: We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. RESULTS: Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family. CONCLUSION: Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.
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