Coding Sequence Mutations Identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 Patients with Familial or Idiopathic Dilated Cardiomyopathy
Coding Sequence Mutations Identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 Patients with Familial or Idiopathic Dilated Cardiomyopathy
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DOI：
10.1111/j.1752-8062.2008.00017.x
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发表时间：
2008-05-01
影响因子：
3.9
通讯作者：
Litt, Michael
中科院分区：
文献类型：
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作者：
Hershberger, Ray E.;Parks, Sharie B.;Litt, Michael
背景：据报道，超过 20 个基因可导致特发性和家族性扩张型心肌病 (IDC/FDC)，但其遗传原因的频率仍知之甚少。 方法和结果：收集了 313 名患者的血样并制备了 DNA，其中 183 名患者患有 FDC，130 名患者患有 IDC。基因组 DNA 对 6 个基因进行了双向测序，并通过对其他家庭成员的评估来跟踪突变携带者。我们在 36 名先证者中发现了 31 种独特的蛋白质改变变异（总体占 11.5%），而在 253 名对照受试者（506 条染色体）中未发现这些变异。其中包括 13 名先证者 (4.2%) 具有 12 种 β-肌球蛋白重链 (MYH7) 突变、9 名先证者 (2.9%) 具有 6 种不同的心肌肌钙蛋白 T (TNNT2) 突变、8 名先证者 (2.6%) 具有 7 种不同的心脏钠通道 (SCN5A) 突变、3 名先证者 (1.0%) 具有 3 种 titin-cap 或 telethonin (TCAP) 突变、3 名先证者(1.0%) 具有两个 LIM 结构域结合 3 (LDB3) 突变，以及一名先证者 (0.3%) 具有肌肉 LIM 蛋白 (CSRP3) 突变。四个核苷酸变化不与表型分离和/或不改变保守氨基酸，因此被认为不太可能引起疾病。 11 名先证者的突变被评估为可能致病，21 名先证者的突变被认为可能致病。这 32 名先证者包括 130 名 IDC 患者中的 14 名（10.8%）和 183 名 FDC 患者中的 18 名（9.8%）。结论：这 6 个基因的突变各自占 FDC/IDC 遗传原因的一小部分。对于 IDC 和 FDC，这些基因中可能或可能致病突变的频率相似。
Background: More than 20 genes have been reported to cause idiopathic and familial dilated cardiomyopathy (IDC/FDC), but the frequency of genetic causation remains poorly understood.Methods and Results: Blood samples were collected and DNA prepared from 313 patients, 183 with FDC and 130 with IDC. Genomic DNA underwent bidirectional sequencing of six genes, and mutation carriers were followed up by evaluation of additional family members. We identified in 36 probands, 31 unique protein-altering variants (11.5% overall) that were not identified in 253 control subjects (506 chromosomes). These included 13 probands (4.2%) with 12 beta-myosin heavy chain (MYH7) mutations, nine probands (2.9%) with six different cardiac troponin T (TNNT2) mutations, eight probands (2.6%) carrying seven different cardiac sodium channel (SCN5A) mutations, three probands (1.0%) with three titin-cap or telethonin (TCAP) mutations, three probands (1.0%) with two LIM domain binding 3 (LDB3) mutations, and one proband (0.3%) with a muscle LIM protein (CSRP3) mutation. Four nucleotide changes did not segregate with phentoype and/or did not alter a conserved amino acid and were therefore considered unlikely to be disease-causing. Mutations in 11 probands were assessed as likely disease-causing, and in 21 probands were considered possibly disease-causing. These 32 probands included 14 of the 130 with IDC (10.8%) and 18 of the 183 with FDC (9.8%)Conclusions: Mutations of these six genes each account for a small fraction of the genetic cause of FDC/IDC. The frequency of possible or likely disease-causing mutations in these genes is similar for IDC and FDC.