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

被引：111

作者：

Balci, T. B. ^{[1
]}

Hartley, T. ^{[2
]}

Xi, Y. ^{[2
,3
,4
]}

Dyment, D. A. ^{[1
,2
]}

Beaulieu, C. L. ^{[2
]}

Bernier, F. P. ^{[3
,4
]}

Dupuis, L. ^{[5
]}

Horvath, G. A. ^{[6
,7
]}

Mendoza-Londono, R. ^{[5
]}

Prasad, C. ^{[8
]}

Richer, J. ^{[1
]}

Yang, X. -R. ^{[3
,4
]}

Armour, C. M. ^{[1
]}

Bareke, E. ^{[9
]}

Fernandez, B. A. ^{[10
]}

McMillan, H. J. ^{[2
]}

Lamont, R. E. ^{[3
,4
]}

Majewski, J. ^{[9
]}

Parboosingh, J. S. ^{[3
,4
]}

Prasad, A. N. ^{[8
]}

Rupar, C. A. ^{[8
]}

Schwartzentruber, J. ^{[9
]}

Smith, A. C. ^{[2
]}

Tetreault, M. ^{[9
]}

Innes, A. M. ^{[3
,4
]}

Boycott, K. M. ^{[1
,2
]}

机构：

[1] Childrens Hosp Eastern Ontario, Dept Genet, 401 Smyth Rd, Ottawa, ON K1H 8L1, Canada

[2] Univ Ottawa, Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada

[3] Univ Calgary, Cumming Sch Med, Dept Med Genet, Calgary, AB, Canada

[4] Univ Calgary, Cumming Sch Med, Alberta Childrens Hosp Res Inst, Calgary, AB, Canada

[5] Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON, Canada

[6] Univ British Columbia, Dept Pediat, Div Biochem Dis, Vancouver, BC, Canada

[7] BC Childrens Hosp, Vancouver, BC, Canada

[8] Western Univ, London Hlth Sci Ctr, London, ON, Canada

[9] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[10] Mem Univ Newfoundland, Disciplines Genet & Med, Fac Med, St John, NF, Canada

来源：

CLINICAL GENETICS | 2017年 / 92卷 / 03期

基金：

加拿大健康研究院;

关键词：

blended phenotypes; dual diagnosis; exome sequencing; multiple genetic diseases; rare diseases; MUTATIONS; GENOME; INHERITANCE; ICHTHYOSIS; PHENOTYPES; DISCOVERY;

D O I：

10.1111/cge.12987

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

BackgroundRecent 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. AimsWe 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 & MethodsWe retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. ResultsOf 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. ConclusionOur findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.

引用

页码：281 / 289

页数：9

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