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Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing
T B Balci1, T Hartley2, Y Xi2,3
1Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
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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