Correlation between clinical characteristics and gene mutation in patients with familial hypertrophic cardiomyopathy
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摘要: 目的 探讨家族性肥厚型心肌病(HCM)先证者的临床特征、预后与基因突变的关系。方法 回顾性分析37例HCM患者的临床以及随访资料，并选择32例患者的外周血样本进行全外显子组测序，筛选潜在的致病基因，进行相应临床评估。结果 37例HCM患者中，男21例，女16例，平均年龄(54.59±16.17)岁，随访5年期间4例患者发生全因死亡，病死率为10.8%；心电图结果提示死亡组患者出现室性期前收缩显著高于存活组(6.0% vs 50.0%，P=0.008)；超声心动图检查提示死亡组患者室间隔厚度显著大于存活组[(18.12±5.26) mm vs (24.25±4.85) mm，P=0.033]。32例患者的基因检测结果共发现20个基因，阳性率43.8%；其中MYBPC3占比最大，且MYBPC3突变更容易发生在男性(87.5%)；其次为MYH7、TTN、ACTN2基因；超声心动图结果中，携带MYBPC3基因的患者左室内径明显大于携带MYH7基因的患者[(41.40±2.88) mm vs (46.50±4.47) mm，P=0.046]。结论 心电图提示室性期前收缩、心脏彩超提示室间隔明显增厚则预后较差；性别对于MYBPC3及MYH7突变具有影响，MYBPC3突变患者左室增大更明显。
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关键词:
- 肥厚型心肌病，家族性 /
- 临床表型 /
- 基因型
Abstract: Objective To investigate the relationship between clinical characteristics, prognosis, and gene mutations in probands of familial hypertrophic cardiomyopathy (HCM).Methods Retrospective analysis encompassed clinical data and follow-up information from 37 patients diagnosed with HCM. Additionally, peripheral blood samples were collected from 32 patients to undergo whole exome sequencing, enabling the identification of potential pathogenic genes and subsequent clinical evaluations. Results Among the cohort of 37 HCM patients, 21 were males and 16 were females, with a mean age of (54.59 ± 16.17) years. Over the course of a 5-year follow-up period, 4 patients succumbed to all-cause mortality, yielding a mortality rate of 10.8%. Electrocardiogram findings highlighted a considerably elevated incidence of ventricular premature beats within the mortality group as opposed to the survival group (6.0% vs 50.0%, P=0.008). Echocardiography outcomes demonstrated a statistically significant augmentation in interventricular septum thickness within the mortality group in contrast to the survival group [(18.12±5.26)mm vs (24.25±4.85)mm, P=0.033]. Genetic analysis of the 32 patients unveiled a spectrum of 20 genes, culminating in a positive detection rate of 43.8%. Notably, MYBPC3 mutations were the most prevalent, predominantly occurring in males (87.5%). Subsequent genes in terms of prevalence were MYH7 , TTN , and ACTN2 genes. Noteworthy findings emerged in the context of echocardiography, revealing that patients carrying the MYBPC3 mutations displayed a notably enlarged left ventricular diameter in comparison to those carrying MYH7 mutation [(41.40±2.88)mm vs (46.50±4.47)mm, P=0.046].Conclusion The prognosis is poor if electrocardiogram indicates ventricular premature beats and heart color Doppler ultrasound indicates obvious thickening of interventricular septum. Gender emerges as an influential factor in the context of MYBPC3 and MYH7 mutations, whereby patients harboring MYBPC3 mutations exhibit more prominent left ventricular enlargement.-
Key words:
- familial hypertrophic cardiomyopathy /
- clinical phenotype /
- genotype
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表 1 ACMG证据列表
Table 1. ACMG evidence
致病性证据 强度 证据 PVS1 极强致病性证据 某些类型的变异(如无义突变、移码突变、±2以内的剪切位点突变、起始密码子突变、单个或多个外显子删除)通常被假定为完全造成基因产物的缺失，导致基因功能的中断 PS1 强致病性证据 有报道同一位置相同氨基酸的改变是一个明确的致病变异 PS2 强致病性证据 在亲缘关系确实的先证者双亲基因中未发现本变异，即本变异是新发突变 PS3 强致病性证据 有良好的功能验证实验表明本变异对蛋白功能造成有害影响 PS4 强致病性证据 对该疾病的群体研究显示，本变异在患者群体中的频率显著高于在正常人群体中的频率 PM1 中等致病性证据 本变异处在一个致病变异的热点区域，或在一个研究完善的功能区域未发现良性变异。这表示该区域功能极为重要，处在该区域的变异为恶性变异的可能性高 PM2 中等致病性证据 本变异为极罕见变异，在特定人种的人群频率数据库中无记载。极为罕见是致病变异的一种特征 PM3 中等致病性证据 当目标疾病为隐性疾病时，发现本变异与另一个明确的致病变异处在反式排列位置上 PM4 中等致病性证据 该变异造成了一个非重复区的非移码插入/缺失，或造成了终止子的丢失 PM5 中等致病性证据 有报道同一位置不同氨基酸的改变是一个明确的致病变异 PM6 中等致病性证据 在先证者双亲基因中未发现本变异，即本变异是新发突变，但亲属关系不明确 PP1 弱致病性证据 在多个家族成员中发现本变异与疾病存在共分离现象 PP2 弱致病性证据 本变异是错义突变，已知错义突变是该基因的一种普遍致病机制，且在基因上的错义突变良性率较低 PP3 弱致病性证据 使用软件对本变异进行蛋白功能预测，多个软件一致预测本变异可能有害 PP4 弱致病性证据 该受检者的表型及(或)家族史高度支持相应疾病的特征 PP5 弱致病性证据 有可靠信誉来源的报道，声称本变异是致病变异 PVS：极强致病；PS：强致病；PM：中等致病；PP：弱致病。 
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表 2 统合规则
Table 2. Rules for combining criteria to classify sequence variants
致病 (1)1个PVS及 ①≥1个PS或 ②≥2个PM或 ③1个PM及1个PP或 ④≥2个PP (2)≥2个PS或 (3)1个PS及 ①≥3个PM或 ②2个PM及≥2个PP或 ③1个PM及≥4个PP 疑似致病 (1)1个PVS及1个PM或 (2)1个PS及1~2个PM或 (3)1个PS及≥2个PP或 (4)≥3个PM或 (5)2个PM及≥2个PP或 (6)1个PM及≥4个PP 意义未明 (1)不符合以上条件或 (2)具有矛盾的良性和恶性证据 注：本文变异致病性的解读遵循ACMG 2015年发布的指南规则。该指南根据变异的功能特征、人群频率、软件预测、历史报道、家族共分离等特征，列举共计27条证据体系匹配，将基因突变按照5级术语系统分类，即致病(Pathogenic)、疑似致病(Likely Pathogenic)、意义未明(Uncertain Significant)、疑似良性(Likely Benign)、良性(Benign)。本文仅涉及致病、疑似致病、意义未明。
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表 3 37例家族性HCM患者的临床基线资料
Table 3. Baseline clinical data in 37 patients with familial HCM
例(%), X±S 项目 整体(37例) 死亡组(4例) 存活组(33例) P 性别 0.175 男 21(56.7) 1(25.0) 20(60.6) 女 16(43.3) 3(75.0) 13(39.4) 年龄/岁 54.59±16.17 66±11.74 53.21±16.21 0.137 心率/(次/min) 82.22±22.48 76±16.67 82.97±23.17 0.566 收缩压/mmHg 125.73±22.85 129.75±32.02 125.24±22.12 0.715 舒张压/mmHg 76.03±11.66 76.5±7.18 75.97±12.17 0.933 NYHA心功能分级 0.737 Ⅰ 14(37.8) 1(25.0) 13(39.4) Ⅱ 12(32.4) 1(25.0) 11(33.3) Ⅲ 10(27.0) 2(50.0) 8(24.2) Ⅳ 1(2.7) 0 1(3.0) 临床症状 晕厥或黑曚 6(16.2) 1(25.0) 5(15.1) 0.614 梗阻性HCM 15(40.5) 3(75.0) 12(36.3) 0.137 心尖型HCM 5(13.5) 1(25.0) 4(12.1) 0.477 脑梗死 2(5.4) 1(25.0) 1(3.0) 0.066 既往史 高血压病 12(32.4) 2(50.0) 10(30.3) 0.427 高脂血症 2(5.4) 0 2(6.0) 0.613 冠心病 9(24.3) 2(50.0) 7(21.2) 0.205 心电图检查结果 QRS间期/ms 103.7±24.19 107.25±21.86 103.27±24.74 0.761 房室传导阻滞 1(2.7) 0 1(3.0) 0.724 室性期前收缩 4(10.8) 2(50.0) 2(6.0) 0.008 心房颤动 8(21.6) 1(25.0) 7(21.2) 0.862 超声心动图结果 左室射血分数/% 70.38±9.57 71.5±7.59 70.24±9.88 0.808 左房内径/mm 40.95±7.18 40.25±6.39 41.03±7.35 0.841 左室内径/mm 43.16±6.07 46±9.12 42.82±5.70 0.329 右室内径/mm 20.16±2.82 19.5±2.38 20.24±2.89 0.626 室间隔厚度/mm 18.78±5.50 24.25±4.85 18.12±5.26 0.033 药物使用情况 β受体阻滞剂 22(59.4) 3(75.0) 19(57.5) 0.503 ACEI 4(10.8) 1(25.0) 3(9.0) 0.333 利尿剂 11(29.7) 1(25.0) 10(30.3) 0.827 起搏器植入 普通起搏器 3(8.1) 1(25.0) 2(6.0) 0.190 ICD 2(5.4) 0 2(6.0) 0.613 1 mmHg=0.133 kPa；ACEI：血管紧张素转化酶抑制剂；ICD：植入型心律转复除颤器。
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表 4 32例家族性HCM患者致病基因突变检测结果
Table 4. Pathogenic gene mutations in 32 patients with familial HCM
基因名称 外显子 核苷酸变异 氨基酸改变 突变类型 患者例数 致病性证据及Clinvar报道 MYH7 17 c.1987C>T p.Arg663Cys 错义 1 PS+2PM+3PP
Clinvar报道致病或疑似致病22 c.2770G>A p.Glu924Lys 错义 1 2PS+PM+5PP
Clinvar报道11致病/2疑似致病9 c.746G>A p.Arg249Gln 错义 1 2PS+PM+2PP
Clinvar报道致病或疑似致病MYBPC3 15 c.1303C>T p.Gln435* 无义突变 1 PVS+PM+2PP
Clinvar报道致病17 c.1595delG p.Gly532fs 移码 1 PVS+PM+2PP
Clinvar报道致病27 c.2827C>T p.Arg943* 无义突变 1 PVS+PS+PM+2PP
Clinvar报道致病32 c.3624delC p.Lys1209fs 移码 2 PVS+PM+2PP
Clinvar报道致病7 c.821+1G>A . 剪切突变 1 PVS+PM+2PP
Clinvar报道致病CALR3 3 c.285C>A p.Tyr95* 无义突变 1 PVS+PM+2PP ACTN2 9 c.824delA p.Asp275fs 移码 2 PVS+PM+2PP
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表 5 32例家族性HCM患者疑似致病基因突变检测结果
Table 5. Likely pathogenic gene mutations in 32 patients with familial HCM
基因名称 外显子 核苷酸变异 氨基酸改变 突变类型 患者例数 致病性证据及Clinvar报道 MYBPC3 17 c.1504C>T p.Arg502Trp 错义 1 2PM+4PP
Clinvar报道疑似致病TNNI3 8 c.557G>A p.Arg186Gln 错义 1 2PM+3PP
Clinvar报道致病或疑似致病TNNT2 10 c.300C>G p.Ile100Met 错义 1 2PM+3PP
Clinvar对该变异上下游±20 bp的14个错义变异报道为8致病/疑似致病，6意义未明TNNI3K 8 c.811G>T p.Gly271* 无义 1 PVS+PM
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表 6 32例家族性HCM患者意义未明基因突变检测结果
Table 6. Uncertain significant gene mutations in 32 patients with familial HCM
基因名称 外显子 核苷酸变异 氨基酸改变 突变类型 患者例数 致病性证据及Clinvar报道 TTN 45 c.10634C>T p.Ala 3545Val 错义 1 PM+PP 342 c.94952A>T p.Lys 31651Ile 错义 1 PM+PP 276 c.52853G>A p.Arg 17618His 错义 1 PM+PP 245 c.45089A>C p.Glu 15030Ala 错义 1 PM+PP 62 c.18143A>G p.Asp 6048Gly 错义 1 PM+PP MYPN 19 c.3553 G>A p.Glu 1185Lys 错义 1 PM+PP 3 c.865G>A p.Asp 289Asn 错义 1 PM+PP ALPK3 4 c.956_ 958del TGG p.Leu 319_Asp320delinsHis 破坏性非移码缺失 1 2PM+PP 10 c.4897 G>A p.Gly 1633Arg 错义 1 PM+PP RYR2 37 c.4990 G>A p.Val 1664Ile 错义 1 PM+2PP 91 c.1213 4T>G p.Leu 4045Trp 错义 1 PM+2PP PRDM16 15 c.3304 G>A p.Val 1102Met 错义 1 PP 9 c.2065 G>A p.Ala 689Thr 错义 1 PP MYH7 15 c.1742 A>G p.His 581Arg 错义 1 PM+2PP 29 c.3974 C>T p.Ala 1325Val 错义 1 PM+2PP 38 c.5704 G>C p.Glu 1902Gln 错义 1 PM+PP SCN5A 2 c.22C>T p.Arg 8Trp 错义 1 PM+PP LAMA4 39 c.5446 A>C p.Ser 1816Arg 错义 1 PM+PP MKRN2 8 c.1162 C>T p.Arg 388Trp 错义 1 PM+2PP NEXN 9 c.1012G>C p.Glu 338Gln 错义 1 PM+PP MYBPC3 15 c.1303C>T p.Gln435* 无义 1 PM+2PP TMPO 2 c.392C>T p.Pro131Leu 错义 1 PM+2PP ANK2 39 c.5747 C>T p.Ser 1916Leu 错义 1 PM FLNC 17 c.2566 C>T p.Pro 856Ser 错义 1 PM+2PP PKP2 1 c.928G>A p.Val 310Met 错义 1 PP
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表 7 携带MYBPC3突变和MYH7突变患者的临床特征
Table 7. Clinical characteristics of patients with MYBPC3 and MYH7 mutations
例(%), X±S 项目 携带MYBPC3基因(8例) 携带MYH7基因(5例) P 性别 0.015 男 7(87.5) 1(20.0) 女 1(12.5) 4(80.0) 年龄/岁 55.38±8.58 53.80±13.95 0.804 心率/(次/min) 76.50±8.50 80.20±7.32 0.440 收缩压/mmHg 113.75±12.71 121.00±16.76 0.393 舒张压/mmHg 81.75±8.87 72.60±5.12 0.062 NYHA心功能分级 0.710 Ⅰ 3(37.5) 1(20.0) Ⅱ 3(37.5) 3(60.0) Ⅲ 1(12.5) 1(20.0) Ⅳ 1(12.5) 0 临床症状 晕厥或黑曚 1(12.5) 0 0.411 梗阻性HCM 4(50.0) 1(20.0) 0.279 心尖型HCM 1(12.5) 0 0.411 脑梗死 0 0 既往史 高血压病 1(12.5) 0 0.411 高脂血症 1(12.5) 0 0.411 冠心病 1(12.5) 1(20.0) 0.649 心电图检查结果 QRS间期/ms 106.53±21.44 101.2±6.14 0.519 房室传导阻滞 0 0 室性期前收缩 1(12.5) 0 0.411 心房颤动 3(37.5) 1(20.0) 0.506 超声心动图结果 左室射血分数/% 66.13±15.79 73.00±7.58 0.388 左房内径/mm 46.13±10.64 38.80±7.82 0.213 左室内径/mm 46.50±4.47 41.40±2.88 0.046 右室内径/mm 19.38±3.92 20.00±3.00 0.767 室间隔厚度/mm 19.25±4.33 18.2.±2.28 0.630 药物使用情况 β受体阻滞剂 4(50.0) 3(60.0) 0.725 ACEI 0 1(20.0) 0.188 利尿剂 3(37.5) 1(20.0) 0.506 起搏器植入 普通起搏器 1(12.5) 0 0.411 ICD植入 0 0 氨基酸改变 错义 2 5 0.008 移码 3 0 0.376 剪切 1 0 0.411 无义 2 0 0.224
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[1] Liu W, Wei Z, Zhang Y, et al. Identification of three novel pathogenic mutations in sarcomere genes associated with familial hypertrophic cardiomyopathy based on multi-omics study[J]. Clin Chim Acta, 2021, 520: 43-52. doi: 10.1016/j.cca.2021.05.034
[2] 吴桂鑫, 邹玉宝, 康连鸣, 等. 《2020年AHA/ACC肥厚型心肌病诊断及治疗指南》解读[J]. 中国分子心脏病学杂志, 2020, 20(6): 3594-3597. doi: 10.16563/j.cnki.1671-6272.2020.12.002
[3] Ko C, Arscott P, Concannon M, et al. Genetic testing impacts the utility of prospective familial screening in hypertrophic cardiomyopathy through identification of a nonfamilial subgroup[J]. Genet Med, 2018, 20(1): 69-75. doi: 10.1038/gim.2017.79
[4] Maron BJ, Maron MS, Maron BA, et al. Moving Beyond the Sarcomere to Explain Heterogeneity in Hypertrophic Cardiomyopathy: JACC Review Topic of the Week[J]. J Am Coll Cardiol, 2019, 73(15): 1978-1986. doi: 10.1016/j.jacc.2019.01.061
[5] Ullal AJ, Abdelfattah RS, Ashley EA, et al. Hypertrophic Cardiomyopathy as a Cause of Sudden Cardiac Death in the Young: A Meta-Analysis[J]. Am J Med, 2016, 129(5): 486-496. e2. doi: 10.1016/j.amjmed.2015.12.027
[6] 范一宁, 姜克新. 超声心动图评价肥厚型心肌病患者升主动脉弹性的价值[J]. 临床心血管病杂志, 2019, 35(2): 141-144. https://lcxxg.whuhzzs.com/article/doi/10.13201/j.issn.1001-1439.2019.02.011
[7] 刘晓曼, 杨广, 李虹, 等. 心脏型肌球蛋白结合蛋白C基因c. 2469-3-4insAG和c. 2469-5-6insT突变与肥厚型心肌病的关系[J]. 中国心血管病研究, 2019, 17(7): 647-650. doi: 10.3969/j.issn.1672-5301.2019.07.016
[8] 顾继伟, 刘春莲, 刘利, 等. 家族性肥厚型心肌病一家系临床资料及健康管理策略分析[J]. 山东医药, 2020, 60(23): 63-66. doi: 10.3969/j.issn.1002-266X.2020.23.017
[9] Cao Y, Zhang PY. Review of recent advances in the management of hypertrophic cardiomyopathy[J]. Eur Rev Med Pharmacol Sci, 2017, 21(22): 5207-5210.
[10] Pascoe SJ. Clinical Course and Management of Hypertrophic Cardiomyopathy[J]. N Engl J Med, 2018, 379(20): 1976-1977. doi: 10.1056/NEJMc1812159
[11] Geisterfer-Lowrance AA, Kass S, Tanigawa G, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation[J]. Cell, 1990, 62(5): 999-1006. doi: 10.1016/0092-8674(90)90274-I
[12] Watkins H, Conner D, Thierfelder L, et al. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy[J]. Nat Genet, 1995, 11(4): 434-437. doi: 10.1038/ng1295-434
[13] Feng X, He T, Wang JG, et al. Asn391Thr Mutation of β-Myosin Heavy Chain in a Hypertrophic Cardiomyopathy Family[J]. Int Heart J, 2018, 59(3): 596-600. doi: 10.1536/ihj.17-250
[14] 吴桂鑫, 朱小辉, 关硕, 等. 肥厚型心肌病MYH7基因致病突变的产前遗传诊断研究[J]. 中国分子心脏病学杂志, 2020, 20(2): 3273-3276. doi: 10.16563/j.cnki.1671-6272.2020.04.001
[15] Seeger T, Shrestha R, Lam CK, et al. A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay[J]. Circulation, 2019, 139(6): 799-811. doi: 10.1161/CIRCULATIONAHA.118.034624
[16] 张小慢, 吴桂鑫, 王虎. 比较携带MYH7基因突变和携带MYBPC3基因突变的肥厚型心肌病患者临床特点及预后[J]. 中国分子心脏病学杂志, 2018, 18(1): 2376-2378. doi: 10.16563/j.cnki.1671-6272.2018.02.013
[17] Velicki L, Jakovljevic DG, Preveden A, et al. Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy[J]. BMC Cardiovasc Disord, 2020, 20(1): 516. doi: 10.1186/s12872-020-01807-4
[18] Carrier L, Mearini G, Stathopoulou K, et al. Cardiac myosin-binding protein C(MYBPC3) in cardiac pathophysiology[J]. Gene, 2015, 573(2): 188-197. doi: 10.1016/j.gene.2015.09.008
[19] McKenna WJ, Judge DP. Epidemiology of the inherited cardiomyopathies[J]. Nat Rev Cardiol, 2021, 18(1): 22-36. doi: 10.1038/s41569-020-0428-2
[20] Sohn DW, Kim HK, Kim YJ, et al. Erratum: Cardiomyopathies with Mixed and Inapparent Morphological Features in Cardiac Troponin I3 Mutation[J]. Korean Circ J, 2017, 47(4): 540. doi: 10.4070/kcj.2016.0445
[21] 陶琴, 何萍萍, 杨俊华, 等. TNNI3基因Arg186Gln突变与家族性肥厚型心肌病的相关性分析[J]. 临床心血管病杂志, 2018, 34(5): 445-448. https://lcxxg.whuhzzs.com/article/doi/10.13201/j.issn.1001-1439.2018.05.005
[22] De Bortoli M, Vio R, Basso C, et al. Novel Missense Variant in MYL2 Gene Associated With Hypertrophic Cardiomyopathy Showing High Incidence of Restrictive Physiology[J]. Circ Genom Precis Med, 2020, 13(2): e002824. doi: 10.1161/CIRCGEN.119.002824
[23] Rosenzweig A, Watkins H, Hwang DS, et al. Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes[J]. N Engl J Med, 1991, 325(25): 1753-1760. doi: 10.1056/NEJM199112193252501
[24] Posen BM, Moolman JC, Corfield VA, et al. Clinical and prognostic evaluation of familial hypertrophic cardiomyopathy in two South African families with different cardiac beta myosin heavy chain gene mutations[J]. Br Heart J, 1995, 74(1): 40-46. doi: 10.1136/hrt.74.1.40
[25] Watkins H, Rosenzweig A, Hwang DS, et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy[J]. N Engl J Med, 1992, 326(17): 1108-1114. doi: 10.1056/NEJM199204233261703
[26] Tajsharghi H, Leren TP, Abdul-Hussein S, et al. Unexpected myopathy associated with a mutation in MYBPC3 and misplacement of the cardiac myosin binding protein C[J]. J Med Genet, 2010, 47(8): 575-577. doi: 10.1136/jmg.2009.072710
[27] Wessels MW, Herkert JC, Frohn-Mulder IM, et al. Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects[J]. Eur J Hum Genet, 2015, 23(7): 922-928. doi: 10.1038/ejhg.2014.211
[28] Li M, Cheng K, Wang QB, et al. Link between cardiac myosin binding protein-C gene mutation of Pro1208fs and Gly507 Arg and hypertrophic cardiomyopathy in Chinese patients[J]. Zhonghua Xin Xue Guan Bing Za Zhi, 2009, 37(9): 790-793.
[29] Erdmann J, Raible J, Maki-Abadi J, et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy[J]. J Am Coll Cardiol, 2001, 38(2): 322-330.
[30] 舒甜, 胡豪畅, 沈才杰, 等. 肥厚型心肌病基因型-表型关联研究进展[J]. 遗传, 2022, 44(3): 198-207. https://www.cnki.com.cn/Article/CJFDTOTAL-YCZZ202203002.htm
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