Role of Titin Missense Variants in Dilated Cardiomyopathy.
Role of Titin Missense Variants in Dilated Cardiomyopathy.
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DOI：
10.1161/jaha.115.002645
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发表时间：
2015-11-13
影响因子：
5.4
通讯作者：
Familial Cardiomyopathy Registry
中科院分区：
文献类型：
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作者：
Begay RL;Graw S;Sinagra G;Merlo M;Slavov D;Gowan K;Jones KL;Barbati G;Spezzacatene A;Brun F;Di Lenarda A;Smith JE;Granzier HL;Mestroni L;Taylor M;Familial Cardiomyopathy Registry
肌联蛋白基因（TTN）编码人类最大的蛋白质，在肌节组织和被动肌细胞僵硬中起着核心作用。TTN截短突变会导致扩张型心肌病（DCM）;然而，由于背景TTN变异的存在，TTN错义变体在扩张型心肌病中的作用一直难以阐明。一组147名DCM指数受试者接受了涵盖TTN心脏亚型N2 B和N2 BA的313个TTN外显子的DNA测序。在348个错义变异中，我们通过在37个先证者中使用生物信息学过滤过程确定了44个“严重”罕见变异。其中，5名先证者为双杂合子（另一DCM基因中的额外变体），7名为复合杂合子（2名TTN“重度”变体）。分离分析允许将“重度”变异分为5种“可能”（共分离）、5种“不太可能”（非共分离）和34种“可能”（其中家族结构排除分离分析）致病变异。携带“可能”或“可能”致病性TTN“重度”变异的DCM患者与“不太可能”和非携带“重度”TTN变异的患者相比，没有显示出不同的结局。然而，“可能”和“可能”致病变异在肌节A带区域的C区中过度表达。 TTN错义变体是常见的，并且对生物信息学分类提出了挑战，特别是当信息家族不可用时。尽管携带生物信息学上“严重”TTN变体的DCM患者的临床病程似乎并不比非携带者更差，但“可能”和“可能”致病变体的非随机分布表明一些TTN错义变体具有潜在的生物学作用。
The titin gene (TTN) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness. TTN truncating mutations cause dilated cardiomyopathy (DCM); however, the role of TTN missense variants in DCM has been difficult to elucidate because of the presence of background TTN variation. A cohort of 147 DCM index subjects underwent DNA sequencing for 313 TTN exons covering the N2B and N2BA cardiac isoforms of TTN. Of the 348 missense variants, we identified 44 “severe” rare variants by using a bioinformatic filtering process in 37 probands. Of these, 5 probands were double heterozygotes (additional variant in another DCM gene) and 7 were compound heterozygotes (2 TTN “severe” variants). Segregation analysis allowed the classification of the “severe” variants into 5 “likely” (cosegregating), 5 “unlikely” (noncosegregating), and 34 “possibly” (where family structure precluded segregation analysis) disease‐causing variants. Patients with DCM carrying “likely” or “possibly” pathogenic TTN “severe” variants did not show a different outcome compared with “unlikely” and noncarriers of a “severe” TTN variant. However, the “likely” and “possibly” disease‐causing variants were overrepresented in the C‐zone of the A‐band region of the sarcomere. TTN missense variants are common and present a challenge for bioinformatic classification, especially when informative families are not available. Although DCM patients carrying bioinformatically “severe” TTN variants do not appear to have a worse clinical course than noncarriers, the nonrandom distribution of “likely” and “possibly” disease‐causing variants suggests a potential biological role for some TTN missense variants.