Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole‐exome sequencing. Issue 3 (13th March 2017)

• Record Type: Journal Article
• Authors: Balci, T.B.; Hartley, T.; Xi, Y.; Dyment, D.A.; Beaulieu, C.L.; Bernier, F.P.; Dupuis, L.; Horvath, G.A.; Mendoza‐Londono, R.; Prasad, C.; Richer, J.; Yang, X.‐R.; Armour, C.M.; Bareke, E.; Fernandez, B.A.; McMillan, H.J.; Lamont, R.E.; Majewski, J.; Parboosingh, J.S.; Prasad, A.N.; Rupar, C.A.; Schwartzentruber, J.; Smith, A.C.; Tétreault, M.; Innes, A.M.; Boycott, K.M.
• Is Part Of: Clinical genetics. Volume 92:Issue 3(2017)
• Page Start: 281
• Page End: 289
• Publication Date: 2017-03-13
• Subjects: blended phenotypes -- dual diagnosis -- exome sequencing -- multiple genetic diseases -- rare diseases; Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.12987
• Languages: English
• ISSNs: 0009-9163

Abstract

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. Abstract :