Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives

Paal Skytt Andersen; Ole Havndrup; Lotte Hougs; Karina M Sørensen; Morten Jensen; Lars Allan Larsen; Paula Hedley; Alex Rojas Bie Thomsen; Johanna Moolman-Smook; Michael Christiansen; Henning Bundgaard

doi:10.1002/humu.20862

Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives

Paal Skytt Andersen, Ole Havndrup, Lotte Hougs, Karina M Sørensen, Morten Jensen, Lars Allan Larsen, Paula Hedley, Alex Rojas Bie Thomsen, Johanna Moolman-Smook, Michael Christiansen, Henning Bundgaard

88 Citations (Scopus)

Abstract

The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM-causing mutations were detected in 32 index patients. Six patients carried two disease-associated mutations. Twenty-two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM-related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow-up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation-screening was superior to clinical investigation in identification of individuals not at increased risk, where follow-up is redundant, but should be offered in all families with relatives at risk for developing HCM. Hum Mutat 0,1-8, 2008. (c) 2008 Wiley-Liss, Inc.

Original language	English
Journal	Human Mutation
Volume	30
Issue number	3
Pages (from-to)	363-370
Number of pages	7
ISSN	1059-7794
DOIs	https://doi.org/10.1002/humu.20862
Publication status	Published - 2008

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Andersen, P. S., Havndrup, O., Hougs, L., Sørensen, K. M., Jensen, M., Larsen, L. A., Hedley, P., Bie Thomsen, A. R., Moolman-Smook, J., Christiansen, M., & Bundgaard, H. (2008). Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives. Human Mutation, 30(3), 363-370. https://doi.org/10.1002/humu.20862

Andersen, PS, Havndrup, O, Hougs, L, Sørensen, KM, Jensen, M, Larsen, LA, Hedley, P, Bie Thomsen, AR, Moolman-Smook, J, Christiansen, M & Bundgaard, H 2008, 'Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives', Human Mutation, vol. 30, no. 3, pp. 363-370. https://doi.org/10.1002/humu.20862

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title = "Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives",

abstract = "The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM-causing mutations were detected in 32 index patients. Six patients carried two disease-associated mutations. Twenty-two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM-related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow-up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation-screening was superior to clinical investigation in identification of individuals not at increased risk, where follow-up is redundant, but should be offered in all families with relatives at risk for developing HCM. Hum Mutat 0,1-8, 2008. (c) 2008 Wiley-Liss, Inc.",

author = "Andersen, {Paal Skytt} and Ole Havndrup and Lotte Hougs and S{\o}rensen, {Karina M} and Morten Jensen and Larsen, {Lars Allan} and Paula Hedley and {Bie Thomsen}, {Alex Rojas} and Johanna Moolman-Smook and Michael Christiansen and Henning Bundgaard",

year = "2008",

doi = "10.1002/humu.20862",

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TY - JOUR

T1 - Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives

AU - Andersen, Paal Skytt

AU - Havndrup, Ole

AU - Hougs, Lotte

AU - Sørensen, Karina M

AU - Jensen, Morten

AU - Larsen, Lars Allan

AU - Hedley, Paula

AU - Bie Thomsen, Alex Rojas

AU - Moolman-Smook, Johanna

AU - Christiansen, Michael

AU - Bundgaard, Henning

PY - 2008

Y1 - 2008

N2 - The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM-causing mutations were detected in 32 index patients. Six patients carried two disease-associated mutations. Twenty-two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM-related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow-up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation-screening was superior to clinical investigation in identification of individuals not at increased risk, where follow-up is redundant, but should be offered in all families with relatives at risk for developing HCM. Hum Mutat 0,1-8, 2008. (c) 2008 Wiley-Liss, Inc.

AB - The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM-causing mutations were detected in 32 index patients. Six patients carried two disease-associated mutations. Twenty-two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM-related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow-up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation-screening was superior to clinical investigation in identification of individuals not at increased risk, where follow-up is redundant, but should be offered in all families with relatives at risk for developing HCM. Hum Mutat 0,1-8, 2008. (c) 2008 Wiley-Liss, Inc.

U2 - 10.1002/humu.20862

DO - 10.1002/humu.20862

M3 - Journal article

C2 - 19035361

SN - 1059-7794

VL - 30

SP - 363

EP - 370

JO - Human Mutation

JF - Human Mutation

IS - 3

ER -

Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives

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