Bottillo Irene, D'Angelantonio Daniela, Caputo Viviana, Paiardini Alessandro, Lipari Martina, De Bernardo Carmelilia, Giannarelli Diana, Pizzuti Antonio, Majore Silvia, Castori Marco, Zachara Elisabetta, Re Federica, Grammatico Paola
Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy.
Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy.
Gene. 2016 Feb 15;577(2):227-35. doi: 10.1016/j.gene.2015.11.048. Epub 2015 Dec 2.
Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder characterized by unexplained left ventricle hypertrophy associated with non-dilated ventricular chambers. Several genes encoding heart sarcomeric proteins have been associated to HCM, but a small proportion of HCM patients harbor alterations in other non-sarcomeric loci. The variable expression of HCM seems influenced by genetic modifier factors and new sequencing technologies are redefining the understanding of genotype-phenotype relationships, even if the interpretations of the numerous identified variants pose several challenges.
We investigated 62 sarcomeric and non-sarcomeric genes in 41 HCM cases and in 3 HCM-related disorders patients. We employed an integrated approach that combines multiple tools for the prediction, annotation and visualization of functional variants. Genotype-phenotype correlations were carried out for inspecting the involvement of each gene in age onset and clinical variability of HCM. The 80% of the non-syndromic patients showed at least one rare non-synonymous variant (nsSNV) and among them, 58% carried alterations in sarcomeric loci, 14% in desmosomal and 7% in other non-sarcomeric ones without any sarcomere change. Statistical analyses revealed an inverse correlation between the number of nsSNVs and age at onset, and a relationship between the clinical variability and number and type of variants.
Our results extend the mutational spectrum of HCM and contribute in defining the molecular pathogenesis and inheritance pattern(s) of this condition. Besides, we delineate a specific procedure for the identification of the most likely pathogenetic variants for a next generation sequencing approach embodied in a clinical context.
肥厚型心肌病（HCM）是一种常见的遗传性心脏疾病，其特征为原因不明的左心室肥厚，且心室腔不扩张。多个编码心脏肌节蛋白的基因已被证实与HCM相关，但仍有一小部分HCM患者在其他非肌节基因座存在改变。HCM的可变表达似乎受遗传修饰因子影响，尽管众多已鉴定变异的解读带来了诸多挑战，但新的测序技术正在重新定义对基因型 - 表型关系的理解。
我们对41例HCM患者和3例HCM相关疾病患者的62个肌节和非肌节基因进行了研究。我们采用了一种综合方法，结合多种工具对功能变异进行预测、注释和可视化。进行基因型 - 表型相关性分析，以检查每个基因在HCM发病年龄和临床变异性中的作用。80%的非综合征患者至少有一个罕见的非同义变异（nsSNV），其中58%的变异发生在肌节基因座，14%发生在桥粒基因座，7%发生在其他非肌节基因座且无任何肌节改变。统计分析显示nsSNV数量与发病年龄呈负相关，临床变异性与变异数量及类型之间存在关联。
我们的结果扩展了HCM的突变谱，有助于明确该病的分子发病机制和遗传模式。此外，我们描绘了一种特定程序，用于识别临床背景下下一代测序方法中最可能的致病变异。
