背景:已经在许多产后队列中研究了遗传变异对先天性心脏病(CHDs)的影响,但在少数产前胎儿队列中进行了描述。总的来说,在不同的产前队列研究中,导致CHD的特定遗传变异,尤其是拷贝数变异(CNV)有一定差异.在这项研究中,在过去的5年中,从三个单位共招募了1118名确诊为CHD的胎儿,组成961例单胎妊娠和157例双胎妊娠。我们对所有病例进行了染色体微阵列分析,以检测数字染色体异常(NCA)和致病性/可能致病性CNVs(P/LPCNVs),并对一些没有NCA和P/LPCNVs的病例进行了全外显子组测序,以检测P/LP序列变异(P/LPSVs)。
结果:总体而言,在17.6%(197/1118)的病例中发现了NCA和P/LPCNVs,NCA占9.1%(102/1118),P/LPCNV占8.5%(95/1118)。非孤立性CHD的NCA频率明显高于孤立性CHD(27.3%vs.4.4%,p<0.001),但分离和非分离CHD之间的P/LPCNVs频率没有显着差异(11.7%vs.7.7%)。在95个胎儿中总共鉴定出109个P/LPCNVs,由97(89.0%)从头组成,6(5.5%)父母遗传,6(5.5%)父母信息不可用。在所有病例的0.9%(10/1118)中检测到16p11.2近端BP4-BP5缺失,仅次于最常见的22q11.21近端A-D缺失(2.1%,23/1118)。检测到的大多数16p11.2缺失(8/10)是从头,与先前研究的对照队列相比,CHD病例中富集。此外,在12.9%(8/62)无NCA和P/LPCNV的病例中发现SV,其中大多数是常染色体显性遗传的从头遗传。
结论:我们的队列研究提供了遗传变异对单胎和双胎CHD的贡献的深度描述;NCA和P/LPCNV对胎儿CHD的贡献为9.1%和8.5%,分别。我们确认16p11.2缺失为CHD相关热点CNV,仅次于22q11.21的删除频率。检测到的大多数16p11.2缺失是从头的。此外,在12.9%(8/62)无NCA或P/LPCNV的胎儿中鉴定出P/LPSV。
BACKGROUND: The contribution of genetic variants to congenital heart defects (CHDs) has been investigated in many postnatal cohorts but described in few prenatal fetus cohorts. Overall, specific genetic variants especially copy number variants (CNVs) leading to CHDs are somewhat diverse among different prenatal cohort studies. In this
study, a total of 1118 fetuses with confirmed CHDs were recruited from three units over a 5-year period, composing 961 of singleton pregnancies and 157 of twin pregnancies. We performed chromosomal microarray analysis on all cases to detect numerical chromosomal abnormalities (NCAs) and pathogenic/likely pathogenic CNVs (P/LP CNVs) and employed whole-exome sequencing for some cases without NCAs and P/LP CNVs to detect P/LP sequence variants (P/LP SVs).
RESULTS: Overall, NCAs and P/LP CNVs were identified in 17.6% (197/1118) of cases, with NCA accounting for 9.1% (102/1118) and P/LP CNV for 8.5% (95/1118). Nonisolated CHDs showed a significantly higher frequency of NCA than isolated CHD (27.3% vs. 4.4%, p < 0.001), but there was no significant difference in the frequency of P/LP CNVs between isolated and nonisolated CHD (11.7% vs. 7.7%). A total of 109 P/LP CNVs were identified in 95 fetuses, consisting of 97 (89.0%) de novo, 6 (5.5%) parental inherited and 6 (5.5%) with unavailable parental information. The 16p11.2 proximal BP4-BP5 deletion was detected in 0.9% (10/1118) of all cases, second only to the most common 22q11.21 proximal A-D deletion (2.1%, 23/1118). Most of the 16p11.2 deletions (8/10) detected were de novo, and were enriched in CHD cases compared with a control cohort from a previous
study. Additionally, SV was identified in 12.9% (8/62) of cases without NCA and P/LP CNV, most of which were de novo with autosomal dominant inheritance.
CONCLUSIONS: Our cohort
study provides a deep profile of the contribution of genetic variants to CHDs in both singleton and twin fetuses; NCA and P/LP CNV contribute to 9.1% and 8.5% of CHD in fetuses, respectively. We confirmed the 16p11.2 deletion as a CHD-associated hotspot CNV, second only to the 22q11.21 deletion in frequency. Most 16p11.2 deletions detected were de novo. Additionally, P/LP SV was identified in 12.9% (8/62) of fetuses without NCA or P/LP CNV.