Objective: To analyze the relationship between genotype and clinical phenotype of the MYH7-R453C mutation in five Chinese hypertrophic cardiomyopathy (HCM) families. Methods: A retrospective cohort study was conducted on 527 unrelated HCM probands who were first diagnosed at the First Affiliated Hospital of Air Force Medical University (Xijing Hospital) from February 2014 to July 2018, and the high-throughput whole exome targeted sequencing of 96 genes related to hereditary cardiovascular disease was performed on the probands. The probands carrying the MYH7-R453C mutation were screened out, and their family members carrying the mutation were verified using Sanger sequencing. Healthy individuals without family history of genetic diseases from the same period and ethnicity were recruited as controls. Clinical data such as echocardiography, 12-lead electrocardiogram, and cardiac magnetic resonance imaging of the probands and their family members were collected, and the correlation between patient genotype and clinical phenotype was analyzed. Endpoint or key events were recorded through hospital re-examination or telephone follow-up. Results: The MYH7-R453C mutation was detected in 5 HCM probands, and clinical data and genetic results of 20 family members, including probands, were collected. Among them, 13 carried the MYH7-R453C mutation, of which 12 were diagnosed with HCM, and one child (F1Ⅲ5) experienced early changes of HCM. The seven family members who did not carry the MYH7-R453C mutation had normal echocardiograms and 12-lead electrocardiograms. Among the 12 patients diagnosed with HCM, 2 experienced (F2Ⅱ7, F5Ⅰ2) sudden cardiac death, 2 experienced (F1Ⅲ1, F3Ⅲ3) events of sudden cardiac death survival, 2(F1Ⅱ2, F3Ⅱ1) died from heart failure during the follow-up period. Combined with the initial visit and follow-up, 4 families (F1, F2, F3, F5) had a family history of sudden death, among which 3 families probands or multiple family members experiencing sudden death before the age of 30 and adverse outcomes such as implantation of implantable cardioverter-defibrillators after sudden death survival. Conclusions: In the five families with HCM carrying MYH7-R453C mutations, genotype is highly correlated with clinical phenotype, and patients have a high risk of sudden death and poor prognosis. Early diagnosis of individuals carrying the MYH7-R453C gene mutation, both within the patient's family and in the patients themselves, is crucial for initiating early treatment, preventing sudden death, and assessing prognosis.
目的： 分析MYH7-R453C突变在5个中国肥厚型心肌病家系中基因型与临床表型的关系。 方法： 本研究为回顾性队列研究。选取2014年2月到2018年7月在空军军医大学西京医院首次确诊的无血缘关系的肥厚型心肌病先证者527例，对其进行96个遗传性心血管疾病相关基因的全外显子区靶向高通量测序。筛选出携带MYH7-R453C突变的先证者，并用Sanger测序法在家系中进行验证。另收集同时期、同种族、无家族遗传病史的健康体检者作为对照。收集先证者及其家属的超声心动图、十二导联心电图、心脏核磁共振等临床资料，分析患者基因型与临床表型的相关性，通过来院复查或进行电话随访，记录终点或重点事件。 结果： 在5个肥厚型心肌病先证者中检测到MYH7-R453C突变，共收集到包括先证者在内20名家系成员的临床资料及基因结果。13名携带MYH7-R453C突变，其中12例被诊断为肥厚型心肌病患者，1名儿童（F1Ⅲ5）出现肥厚型心肌病早期改变。未携带MYH7-R453C突变的7名家属超声心动图和十二导联心电图均正常。随访期间12例肥厚型心肌病患者中，2例（F2Ⅱ7、F5Ⅰ2）发生心脏性猝死，2例（F1Ⅲ1、F3Ⅲ3）发生猝死生还事件，2例（F1Ⅱ2、F3Ⅱ1）心力衰竭死亡。结合初次就诊和随访情况，4个家系（F1、F2、F3、F5）具有猝死家族史，其中3个家系出现先证者或多个家属小于30岁发生猝死及猝死生还后植入埋藏式心脏复律除颤器等不良预后。 结论： 在携带MYH7-R453C突变的5个肥厚型心肌病家系中基因型与临床表型高度相关，患者具有猝死风险高，预后差的特点，对携带MYH7-R453C基因突变患者及家系成员的早期诊断有助于患者尽早治疗、预防猝死及预后评估。.