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Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.

Publication ,  Journal Article
Miszalski-Jamka, K; Jefferies, JL; Mazur, W; Głowacki, J; Hu, J; Lazar, M; Gibbs, RA; Liczko, J; Kłyś, J; Venner, E; Muzny, DM; Rycaj, J ...
Published in: Circ Cardiovasc Genet
August 2017

BACKGROUND: Left ventricular noncompaction (LVNC) is a genetically and phenotypically heterogeneous disease and, although increasingly recognized in clinical practice, there is a lack of widely accepted diagnostic criteria. We sought to identify novel genetic causes of LVNC and describe genotype-phenotype correlations. METHODS AND RESULTS: A total of 190 patients from 174 families with left ventricular hypertrabeculation (LVHT) or LVNC were referred for cardiac magnetic resonance and whole-exome sequencing. A total of 425 control individuals were included to identify variants of interest (VOIs). We found an excess of 138 VOIs in 102 (59%) unrelated patients in 54 previously identified LVNC or other known cardiomyopathy genes. VOIs were found in 68 of 90 probands with LVNC and 34 of 84 probands with LVHT (76% and 40%, respectively; P<0.001). We identified 0, 1, and ≥2 VOIs in 72, 74, and 28 probands, respectively. We found increasing number of VOIs in a patient strongly correlated with several markers of disease severity, including ratio of noncompacted to compacted myocardium (P<0.001) and left ventricular ejection fraction (P=0.01). The presence of sarcomeric gene mutations was associated with increased occurrence of late gadolinium enhancement (P=0.004). CONCLUSIONS: LVHT and LVNC likely represent a continuum of genotypic disease with differences in severity and variable phenotype explained, in part, by the number of VOIs and whether mutations are present in sarcomeric or nonsarcomeric genes. Presence of VOIs is common in patients with LVHT. Our findings expand the current clinical and genetic diagnostic approaches for patients with LVHT and LVNC.

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Published In

Circ Cardiovasc Genet

DOI

EISSN

1942-3268

Publication Date

August 2017

Volume

10

Issue

4

Location

United States

Related Subject Headings

  • Young Adult
  • Ventricular Dysfunction, Left
  • Tropomyosin
  • Severity of Illness Index
  • Prospective Studies
  • Myosin Heavy Chains
  • Myocardium
  • Muscle Proteins
  • Middle Aged
  • Male
 

Citation

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Miszalski-Jamka, K., Jefferies, J. L., Mazur, W., Głowacki, J., Hu, J., Lazar, M., … Bainbridge, M. N. (2017). Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. Circ Cardiovasc Genet, 10(4). https://doi.org/10.1161/CIRCGENETICS.117.001763
Miszalski-Jamka, Karol, John L. Jefferies, Wojciech Mazur, Jan Głowacki, Jianhong Hu, Monika Lazar, Richard A. Gibbs, et al. “Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.Circ Cardiovasc Genet 10, no. 4 (August 2017). https://doi.org/10.1161/CIRCGENETICS.117.001763.
Miszalski-Jamka K, Jefferies JL, Mazur W, Głowacki J, Hu J, Lazar M, et al. Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. Circ Cardiovasc Genet. 2017 Aug;10(4).
Miszalski-Jamka, Karol, et al. “Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.Circ Cardiovasc Genet, vol. 10, no. 4, Aug. 2017. Pubmed, doi:10.1161/CIRCGENETICS.117.001763.
Miszalski-Jamka K, Jefferies JL, Mazur W, Głowacki J, Hu J, Lazar M, Gibbs RA, Liczko J, Kłyś J, Venner E, Muzny DM, Rycaj J, Białkowski J, Kluczewska E, Kalarus Z, Jhangiani S, Al-Khalidi H, Kukulski T, Lupski JR, Craigen WJ, Bainbridge MN. Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. Circ Cardiovasc Genet. 2017 Aug;10(4).

Published In

Circ Cardiovasc Genet

DOI

EISSN

1942-3268

Publication Date

August 2017

Volume

10

Issue

4

Location

United States

Related Subject Headings

  • Young Adult
  • Ventricular Dysfunction, Left
  • Tropomyosin
  • Severity of Illness Index
  • Prospective Studies
  • Myosin Heavy Chains
  • Myocardium
  • Muscle Proteins
  • Middle Aged
  • Male