Miszalski-Jamka Karol, Jefferies John L, Mazur Wojciech, Głowacki Jan, Hu Jianhong, Lazar Monika, Gibbs Richard A, Liczko Jacek, Kłyś Jan, Venner Eric, Muzny Donna M, Rycaj Jarosław, Białkowski Jacek, Kluczewska Ewa, Kalarus Zbigniew, Jhangiani Shalini, Al-Khalidi Hussein, Kukulski Tomasz, Lupski James R, Craigen William J, Bainbridge Matthew N
Circ Cardiovasc Genet. 2017 Aug;10(4). doi: 10.1161/CIRCGENETICS.117.001763.
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.
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; <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 (<0.001) and left ventricular ejection fraction (=0.01). The presence of sarcomeric gene mutations was associated with increased occurrence of late gadolinium enhancement (=0.004).
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.
左心室心肌致密化不全（LVNC）是一种在遗传和表型上具有异质性的疾病，尽管在临床实践中其被认识的程度日益增加，但仍缺乏广泛接受的诊断标准。我们试图确定LVNC的新遗传病因，并描述基因型与表型的相关性。
来自174个家庭的总共190例患有左心室肌小梁增多（LVHT）或LVNC的患者被转诊进行心脏磁共振成像和全外显子测序。总共纳入了425名对照个体以识别感兴趣的变异（VOIs）。我们在54个先前确定的LVNC或其他已知心肌病基因中的102例（59%）无亲缘关系的患者中发现了138个过量的VOIs。在90例LVNC先证者中有68例发现了VOIs，在84例LVHT先证者中有34例发现了VOIs（分别为76%和40%；<0.001）。我们在72例、74例和28例先证者中分别鉴定出0个、1个和≥2个VOIs。我们发现患者中VOIs数量的增加与疾病严重程度的几个标志物密切相关，包括非致密心肌与致密心肌的比例（<0.001）和左心室射血分数（=0.01）。肌节基因突变的存在与晚期钆增强的发生率增加相关（=0.004）。
LVHT和LVNC可能代表了一种基因型疾病的连续体，其严重程度和可变表型的差异部分由VOIs的数量以及突变是存在于肌节基因还是非肌节基因中所解释。VOIs在LVHT患者中很常见。我们的发现扩展了目前针对LVHT和LVNC患者的临床和基因诊断方法。
