Reproductive Fitness and Genetic Transmission of Tetralogy of Fallot in the Molecular Age
Reproductive Fitness and Genetic Transmission of Tetralogy of Fallot in the Molecular Age
复制标题
DOI：
10.1161/circgenetics.113.000328
复制
发表时间：
2014-04-01
影响因子：
--
通讯作者：
Bassett, Anne S.
中科院分区：
文献类型：
--
作者：
Chin-Yee, Nicolas J.;Costain, Gregory;Bassett, Anne S.
法洛四联症（TOF）患者现在通常存活到生殖年龄及以上。在现代，特别是考虑到最近的分子遗传学发现，TOF成人的生殖适应性和后代的复发风险越来越引起人们的兴趣。方法和结果：在排除了已知遗传综合征的个体后，543名无亲缘关系的TOF成人进行了详细的家族史评估，并使用高分辨率全基因组微阵列对罕见的拷贝数变异进行了分子表征。与没有先天性心脏病的年龄匹配的对照组相比，TOF患者的后代明显减少（P=0.0004）。稀有拷贝数变异负担的任何方面都不能预测生殖适合度的降低。随着现代外科修复术的出现，女性的生殖适宜度开始超过男性（P=0.0490）。子代冠心病的复发风险为4.8%，TOF患者的男性和女性之间无显著差异。后代发生严重冠心病的风险（2.3%）远远超过人群预期（相对风险，15.6；95%可信区间，7.9-31.0）。大多数冠心病的垂直传播病例不能用大量罕见拷贝数变异的传播来解释。虽然圆锥锥体病变（31.5%）是亲属中最常见的冠心病，但家族性疾病谱包括许多解剖学上不一致的病变。结论：TOF患者的生殖健康水平降低。他们的后代患严重冠心病的风险显著增加。这些结果支持遗传咨询对患有复杂冠心病的男性和女性的重要性。许多遗传的基因变异仍有待发现。
Background-Individuals with tetralogy of Fallot (TOF) now routinely survive to reproductive age and beyond. Reproductive fitness of adults with TOF and recurrence risks to offspring are of increasing interest in the modern era, especially given recent molecular genetic discoveries.Methods and Results-After excluding individuals with known genetic syndromes, 543 unrelated adults with TOF underwent a detailed family history assessment and molecular characterization for rare copy number variations using high-resolution genome-wide microarrays. Men and women with TOF had significantly fewer offspring compared with an age-matched comparison group without congenital heart disease (CHD; P=0.0004). No aspect of rare copy number variation burden was a predictor of decreased reproductive fitness. Corresponding with the advent of modern surgical repairs, reproductive fitness of women began to exceed that of men (P=0.0490). Recurrence risk for CHD in offspring was 4.8%, with no significant differences between men and women with TOF. The risk of severe CHD in offspring (2.3%) far exceeded population expectations (relative risk, 15.6; 95% confidence interval, 7.9-31.0). Most cases of vertical transmission of CHD were not explained by the transmission of a large rare copy number variation. Although conotruncal lesions (31.5%) were the most commonly reported CHD in relatives, the familial spectrum of disease included many anatomically discordant lesions.Conclusions-Men and women with TOF have reduced reproductive fitness. Their offspring are at significantly elevated risk for severe CHD. These results support the importance of genetic counseling for both men and women with complex CHD. Many inherited genetic variants remain to be discovered.