Universidade da Coruña, Programa de Doutorado en Ciencias da Saúde, La Coruña, Spain; Departamento de Genética Médica, Health in Code, La Coruña, Spain.
Departamento de Cardiología, Hospital Meixoeiro, Vigo, Pontevedra, Spain.
Rev Esp Cardiol (Engl Ed). 2022 Mar;75(3):242-250. doi: 10.1016/j.rec.2021.01.001. Epub 2021 Feb 26.
TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees.
TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain.
The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect.
TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.
TPM1 是主要的肥厚型心肌病（HCM）基因之一。携带该基因的患者的临床信息相对较少，限制了对个体患者遗传发现的解释。我们的目的是在一系列家系中建立 TPM1 p.Arg21Leu 变异的基因型-表型相关性。
我们对 10561 名患有遗传性心脏病的无血缘关系的患者进行了下一代测序评估 TPM1。通过桑格法进行家族遗传筛查。我们分析了 TPM1 p.Arg21Leu 家系的共分离、临床特征和结果。我们还估计了葡萄牙和西班牙携带者家族的地理分布。
TPM1 p.Arg21Leu 变异在 25/4099（0.61%）HCM 病例中被发现，而在 6462 名患有其他遗传性心脏表型的对照个体中不存在（P<.0001）。总共鉴定出 83 名携带者（31 名先证者）。家族共分离的联合 LOD 得分为 3.95。在男性中，携带者的累积诊断概率为 50 岁时为 50%，女性携带者为 25%。70 岁时，17%的男性和 46%的女性携带者未受影响。平均最大左心室壁厚度为 21.4±7.65mm。计算得出的 34 名携带者（77.5%）的 HCM 猝死风险较低，8 名携带者（18%）的风险中等，仅 2 名携带者（4.5%）的风险较高。50 岁时，无心血管死亡或心脏移植的生存率为 87.5%。6%的携带者为纯合子，18%的携带者有另一个变异。家族起源集中在加利西亚、埃斯特雷马杜拉和葡萄牙北部，提示存在一个起源效应。
TPM1 p.Arg21Leu 是一种致病性的 HCM 变异体，与晚发/不完全外显和总体良好的预后相关。
