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

TitleNovel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.
Publication TypeJournal Article
Year of Publication2017
AuthorsMiszalski-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
JournalCirc Cardiovasc Genet
Date Published2017 Aug
KeywordsAdaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Cardiac Myosins, Carrier Proteins, Child, Connectin, Female, Genetic Association Studies, Genetic Variation, Heart Ventricles, Humans, LIM Domain Proteins, Magnetic Resonance Imaging, Cine, Male, Middle Aged, Muscle Proteins, Myocardium, Myosin Heavy Chains, Prospective Studies, Severity of Illness Index, Tropomyosin, Ventricular Dysfunction, Left, Young Adult

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;

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.

Alternate JournalCirc Cardiovasc Genet
PubMed ID28798025
PubMed Central IDPMC5665372
Grant ListU54 HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States