Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing.
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.


OBJECTIVE
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.


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.


CONCLUSIONS
Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
T B
http://orcid.org/0000-0002-5409-8387
TB
Balci
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
T
T
Hartley
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.|Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
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Y
Xi
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.|Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
D A
DA
Dyment
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
C L
CL
Beaulieu
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
F P
FP
Bernier
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
L
L
Dupuis
Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada.
G A
GA
Horvath
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
R
R
Mendoza-Londono
London Health Sciences Centre, Western University, London, Ontario, Canada.
C
C
Prasad
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
J
J
Richer
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
X-R
XR
Yang
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
C M
CM
Armour
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
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E
Bareke
Disciplines of Genetics and Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
B A
BA
Fernandez
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
H J
HJ
McMillan
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
R E
RE
Lamont
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
J
J
Majewski
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
J S
JS
Parboosingh
London Health Sciences Centre, Western University, London, Ontario, Canada.
A N
AN
Prasad
London Health Sciences Centre, Western University, London, Ontario, Canada.
C A
CA
Rupar
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
J
J
Schwartzentruber
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
A C
AC
Smith
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
M
M
Tétreault
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
A M
AM
Innes
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.|Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
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http://orcid.org/0000-0003-4186-8052
KM
Boycott
D002170:Canada / Q000453:epidemiology; D002675:Child, Preschool; D003241:Consanguinity; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012189:Retrospective Studies; D035781:Siblings; D000073359:Exome Sequencing / Q000379:methods
blended phenotypes; dual diagnosis; exome sequencing; multiple genetic diseases; rare diseases