Programme for Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark.
Eur Heart J. 2018 Mar 21;39(12):1015-1022. doi: 10.1093/eurheartj/ehx314.
Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis.
We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co-occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes.
Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes.
先天性心脏病（CHD）影响了几乎 1%的所有活产儿，且患有 CHD 的成年人数量正在增加。在先前发生 CHD 的家庭中，估计复发风险和复发畸形的类型对于咨询和临床决策很重要，但家庭中的复发模式知之甚少。我们旨在通过调查已知畸形的 1163 个家庭中 CHD 的共发情况，来确定复发模式，这些家庭包括 3080 名经临床确诊的个体。
我们计算了 41 种特定类型畸形的一致性和不一致性发生率，观察到一致性和不一致性发生率的高度可变性。通过计算 1640 对受影响家庭成员之间观察到的不一致病变的每个比值比，我们能够确定 178 对畸形在家庭中发生的频率明显高于或低于预期。数据表明，家族中存在不同类型的心脏畸形共同发生，这表明存在潜在的发育机制影响。对人类和小鼠易感基因的分析表明，它们在共同发生的不一致畸形的配对中分别共享 19%和 20%，但很少共同发生的畸形没有共享，这表明家庭中共同发生的病变的很大一部分是由重叠的易感基因引起的。
家族性 CHD 遵循特定的复发模式，这表明遗传调控的发育机制有很强的影响。家庭中畸形的共发是由共同的易感基因引起的。
