Genetic testing for dilated cardiomyopathy in clinical practice

Neal K. Lakdawala, Birgit H. Funke, Samantha Baxter, Allison L. Cirino, Amy E. Roberts, Daniel P. Judge, Nicole Johnson, Nancy J. Mendelsohn, Chantal Morel, Melanie Care, Wendy K. Chung, Carolyn Jones, Apostolos Psychogios, Elizabeth Duffy, Heidi L. Rehm, Emily White, J. G. Seidman, Christine E. Seidman, Carolyn Y. Ho

Research output: Contribution to journalArticle

Abstract

Background: Familial involvement is common in dilated cardiomyopathy (DCM) and >40 genes have been implicated in causing disease. However, the role of genetic testing in clinical practice is not well defined. We examined the experience of clinical genetic testing in a diverse DCM population to characterize the prevalence and predictors of gene mutations. Methods and Results: We studied 264 unrelated adult and pediatric DCM index patients referred to 1 reference lab for clinical genetic testing. Up to 10 genes were analyzed (MYH7, TNNT2, TNNI3, TPM1, MYBPC3, ACTC, LMNA, PLN, TAZ, and LDB3), and 70% of patients were tested for all genes. The mean age was 26.6 ± 21.3 years, and 52% had a family history of DCM. Rigorous criteria were used to classify DNA variants as clinically relevant (mutations), variants of unknown clinical significance (VUS), or presumed benign. Mutations were found in 17.4% of patients, commonly involving MYH7, LMNA, or TNNT2 (78%). An additional 10.6% of patients had VUS. Genetic testing was rarely positive in older patients without a family history of DCM. Conversely in pediatric patients, family history did not increase the sensitivity of genetic testing. Conclusions: Using rigorous criteria for classifying DNA variants, mutations were identified in 17% of a diverse group of DCM index patients referred for clinical genetic testing. The low sensitivity of genetic testing in DCM reflects limitations in both current methodology and knowledge of DCM-associated genes. However, if mutations are identified, genetic testing can help guide family management.

Original languageEnglish (US)
Pages (from-to)296-303
Number of pages8
JournalJournal of Cardiac Failure
Volume18
Issue number4
DOIs
StatePublished - Apr 2012

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Dilated Cardiomyopathy
Genetic Testing
Mutation
Genes
Pediatrics
DNA
Population

Keywords

  • Clinical genetics
  • dilated cardiomyopathy
  • heart failure
  • lamin A/C
  • sarcomere genes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Lakdawala, N. K., Funke, B. H., Baxter, S., Cirino, A. L., Roberts, A. E., Judge, D. P., ... Ho, C. Y. (2012). Genetic testing for dilated cardiomyopathy in clinical practice. Journal of Cardiac Failure, 18(4), 296-303. https://doi.org/10.1016/j.cardfail.2012.01.013

Genetic testing for dilated cardiomyopathy in clinical practice. / Lakdawala, Neal K.; Funke, Birgit H.; Baxter, Samantha; Cirino, Allison L.; Roberts, Amy E.; Judge, Daniel P.; Johnson, Nicole; Mendelsohn, Nancy J.; Morel, Chantal; Care, Melanie; Chung, Wendy K.; Jones, Carolyn; Psychogios, Apostolos; Duffy, Elizabeth; Rehm, Heidi L.; White, Emily; Seidman, J. G.; Seidman, Christine E.; Ho, Carolyn Y.

In: Journal of Cardiac Failure, Vol. 18, No. 4, 04.2012, p. 296-303.

Research output: Contribution to journalArticle

Lakdawala, NK, Funke, BH, Baxter, S, Cirino, AL, Roberts, AE, Judge, DP, Johnson, N, Mendelsohn, NJ, Morel, C, Care, M, Chung, WK, Jones, C, Psychogios, A, Duffy, E, Rehm, HL, White, E, Seidman, JG, Seidman, CE & Ho, CY 2012, 'Genetic testing for dilated cardiomyopathy in clinical practice', Journal of Cardiac Failure, vol. 18, no. 4, pp. 296-303. https://doi.org/10.1016/j.cardfail.2012.01.013
Lakdawala NK, Funke BH, Baxter S, Cirino AL, Roberts AE, Judge DP et al. Genetic testing for dilated cardiomyopathy in clinical practice. Journal of Cardiac Failure. 2012 Apr;18(4):296-303. https://doi.org/10.1016/j.cardfail.2012.01.013
Lakdawala, Neal K. ; Funke, Birgit H. ; Baxter, Samantha ; Cirino, Allison L. ; Roberts, Amy E. ; Judge, Daniel P. ; Johnson, Nicole ; Mendelsohn, Nancy J. ; Morel, Chantal ; Care, Melanie ; Chung, Wendy K. ; Jones, Carolyn ; Psychogios, Apostolos ; Duffy, Elizabeth ; Rehm, Heidi L. ; White, Emily ; Seidman, J. G. ; Seidman, Christine E. ; Ho, Carolyn Y. / Genetic testing for dilated cardiomyopathy in clinical practice. In: Journal of Cardiac Failure. 2012 ; Vol. 18, No. 4. pp. 296-303.
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abstract = "Background: Familial involvement is common in dilated cardiomyopathy (DCM) and >40 genes have been implicated in causing disease. However, the role of genetic testing in clinical practice is not well defined. We examined the experience of clinical genetic testing in a diverse DCM population to characterize the prevalence and predictors of gene mutations. Methods and Results: We studied 264 unrelated adult and pediatric DCM index patients referred to 1 reference lab for clinical genetic testing. Up to 10 genes were analyzed (MYH7, TNNT2, TNNI3, TPM1, MYBPC3, ACTC, LMNA, PLN, TAZ, and LDB3), and 70{\%} of patients were tested for all genes. The mean age was 26.6 ± 21.3 years, and 52{\%} had a family history of DCM. Rigorous criteria were used to classify DNA variants as clinically relevant (mutations), variants of unknown clinical significance (VUS), or presumed benign. Mutations were found in 17.4{\%} of patients, commonly involving MYH7, LMNA, or TNNT2 (78{\%}). An additional 10.6{\%} of patients had VUS. Genetic testing was rarely positive in older patients without a family history of DCM. Conversely in pediatric patients, family history did not increase the sensitivity of genetic testing. Conclusions: Using rigorous criteria for classifying DNA variants, mutations were identified in 17{\%} of a diverse group of DCM index patients referred for clinical genetic testing. The low sensitivity of genetic testing in DCM reflects limitations in both current methodology and knowledge of DCM-associated genes. However, if mutations are identified, genetic testing can help guide family management.",
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AU - Lakdawala, Neal K.

AU - Funke, Birgit H.

AU - Baxter, Samantha

AU - Cirino, Allison L.

AU - Roberts, Amy E.

AU - Judge, Daniel P.

AU - Johnson, Nicole

AU - Mendelsohn, Nancy J.

AU - Morel, Chantal

AU - Care, Melanie

AU - Chung, Wendy K.

AU - Jones, Carolyn

AU - Psychogios, Apostolos

AU - Duffy, Elizabeth

AU - Rehm, Heidi L.

AU - White, Emily

AU - Seidman, J. G.

AU - Seidman, Christine E.

AU - Ho, Carolyn Y.

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N2 - Background: Familial involvement is common in dilated cardiomyopathy (DCM) and >40 genes have been implicated in causing disease. However, the role of genetic testing in clinical practice is not well defined. We examined the experience of clinical genetic testing in a diverse DCM population to characterize the prevalence and predictors of gene mutations. Methods and Results: We studied 264 unrelated adult and pediatric DCM index patients referred to 1 reference lab for clinical genetic testing. Up to 10 genes were analyzed (MYH7, TNNT2, TNNI3, TPM1, MYBPC3, ACTC, LMNA, PLN, TAZ, and LDB3), and 70% of patients were tested for all genes. The mean age was 26.6 ± 21.3 years, and 52% had a family history of DCM. Rigorous criteria were used to classify DNA variants as clinically relevant (mutations), variants of unknown clinical significance (VUS), or presumed benign. Mutations were found in 17.4% of patients, commonly involving MYH7, LMNA, or TNNT2 (78%). An additional 10.6% of patients had VUS. Genetic testing was rarely positive in older patients without a family history of DCM. Conversely in pediatric patients, family history did not increase the sensitivity of genetic testing. Conclusions: Using rigorous criteria for classifying DNA variants, mutations were identified in 17% of a diverse group of DCM index patients referred for clinical genetic testing. The low sensitivity of genetic testing in DCM reflects limitations in both current methodology and knowledge of DCM-associated genes. However, if mutations are identified, genetic testing can help guide family management.

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KW - heart failure

KW - lamin A/C

KW - sarcomere genes

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