Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York, USA.
Mol Genet Genomic Med. 2022 Jun;10(6):e1944. doi: 10.1002/mgg3.1944. Epub 2022 Apr 28.
While many studies agree that consanguinity increases the rate of congenital heart disease (CHD), few genome analyses have been conducted with consanguineous CHD cohorts.
We recruited 73 CHD probands from consanguineous families in Turkey and used whole-exome sequencing (WES) to identify genetic lesions in these patients.
On average, each patient had 6.95 rare damaging homozygous variants, 0.68 of which are loss-of-function (LoF) variants. Seven patients (9.6%) carried damaging homozygous variants in five causal CHD genes. Six of those patients exhibited laterality defects (six HTX and one D-TGA). Three additional patients (4.1%) harbored other types of CHD-associated genomic alterations, which overall explained 13.7% (10/73) of the cohort. The contribution from recessive variants in our cohort is higher than 1.8% reported from a cohort of 2871 CHD subjects where 5.6% of subjects met the criteria for consanguinity.
Our WES screen of a Turkish consanguineous population with structural CHD revealed its unique genetic architecture. Six of seven damaging homozygous variants in CHD causal genes occur in the setting of laterality defects implies a strong contribution from consanguinity to these defects specifically. Our study thus provided valuable information about the genetic landscape of CHD in consanguineous families in Turkey.
尽管许多研究都认为近亲结婚会增加先天性心脏病 (CHD) 的发病率，但很少有针对近亲结婚的 CHD 队列进行全基因组分析。
我们从土耳其的近亲结婚家庭中招募了 73 名 CHD 先证者，并使用全外显子组测序 (WES) 来鉴定这些患者的遗传病变。
平均每位患者携带 6.95 个罕见的有害纯合变异，其中 0.68 个为功能丧失 (LoF) 变异。7 名患者 (9.6%) 在五个导致 CHD 的基因中携带有害的纯合变异。其中 6 名患者表现出侧位缺陷（6 名 HTX 和 1 名 D-TGA）。另外 3 名患者 (4.1%) 携带其他类型的与 CHD 相关的基因组改变，这些改变总共解释了该队列的 13.7% (10/73)。我们的队列中隐性变异的贡献高于从 2871 名 CHD 患者的队列中报告的 1.8%，其中 5.6%的患者符合近亲结婚的标准。
我们对土耳其有结构 CHD 的近亲结婚人群进行的 WES 筛查揭示了其独特的遗传结构。在导致 CHD 的基因中，7 个有害纯合变异中的 6 个发生在侧位缺陷的情况下，这意味着近亲结婚对这些缺陷有很强的贡献。因此，我们的研究为土耳其近亲结婚家庭的 CHD 遗传图谱提供了有价值的信息。
