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首页> 外文期刊>Circulation. Genomic and precision medicine. >Key Value of RNA Analysis of MYBPC3 Splice-Site Variants in Hypertrophic Cardiomyopathy
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Key Value of RNA Analysis of MYBPC3 Splice-Site Variants in Hypertrophic Cardiomyopathy

机译：键值的RNA分析MYBPC3剪切位点变异在肥厚性心肌病

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BACKGROUND: MYBPC3 splicing errors are a common cause of hypertrophic cardiomyopathy (HCM). Variants affecting essential splicesite dinucleotides inhibit splicing, whereas the impact of variants at conserved flanking nucleotides is less clear. We evaluated the contribution of MYBPC3 splice-site variants in a large cohort of patients with HCM and assessed the impact on splicing with RNA analysis. METHODS: Patients attending a specialized multidisciplinary clinic, with a clinical diagnosis of HCM and genetic testing of at least 46 cardiomyopathy-associated genes, were included. Patients with variants in MYBPC3 splice sites with in silico-predicted effects on splicing were selected. RNA was extracted from fresh venous blood or paraffin-embedded myocardial tissue of the patients, amplified, and sequenced. Variants were classified for pathogenicity using the American College of Medical Genetics and Genomics guidelines. RESULTS: We found 29 rare MYBPC3 splice-site variants in 56 of 557 (10%) unrelated HCM probands. Three variants were not predicted to alter RNA splicing, and 13 essential splice dinucleotide, nonsense, and short insertion or deletion variants were not further assessed. RNA analysis was performed on 9 variants (c.654+5G>C, c.772G>A, c.821+3G>T, c.927-9G>A, c.1090G>A, c.1624G>A, c.1624+4A>T, c.3190+5G>A, and c.3491-3C>G), and RNA splicing errors were confirmed for 7. Four variants in 4 families resulted in clinically meaningful reclassifications. CONCLUSIONS: After RNA analysis, 4 of 56 (7%) families with MYBPC3 splice-site variants were reclassified from uncertain clinical significance to likely pathogenic. RNA analysis of splice-site variants can assist in understanding pathogenicity and increase the diagnostic yield of genetic testing in HCM.
机译：背景:MYBPC3拼接是一个常见的错误肥厚性心肌病(HCM)的原因。变异影响基本splicesite二核苷酸抑制拼接,而在守恒的侧翼变异的影响核苷酸尚不明朗。的贡献MYBPC3剪切位点变异大群HCM患者和评估对与RNA剪接分析的影响。方法:病人参加一个专业临床多学科诊所至少HCM的诊断和基因检测46 cardiomyopathy-associated基因,包括在内。网站在silico-predicted影响拼接。新鲜的静脉血液或石蜡包埋心肌组织的病人、放大和测序。使用美国大学的致病性医学遗传学和基因组学的指导方针。结果:我们发现29个罕见MYBPC3剪切位点557年56变异(10%)HCM无关渊源者。改变RNA拼接,拼接和13必不可少的二核苷酸,胡说八道,插入或短删除变量没有进一步的评估。分析了9变种(c.654 > C + 5克、c . 772G > A, c . 821 + 3G > T, c . 927-9G > A, c . 1090G > A,c . 1624G > A, 4A + c . 1624 > T、c . 3190 + 5G > Ac.3491-3C > G)和RNA拼接错误确认为7。导致临床意义重新分类。分析4与MYBPC3 56例(7%)的家庭剪切位点变异进行分类不确定可能的临床意义致病性。可以帮助了解致病性和基因检测诊断产量增加在HCM .

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