Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York.
Birth Defects Res. 2017 Jan 20;109(1):8-15. doi: 10.1002/bdra.23586.
Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdevelopment of the right heart structures commonly accompanied by an atrial septal defect. Familial HRHS reports suggest genetic factor involvement. We examined the role of copy number variants (CNVs) in HRHS.
We genotyped 32 HRHS cases identified from all New York State live births (1998-2005) using Illumina HumanOmni2.5 microarrays. CNVs were called with PennCNV and prioritized if they were ≥20 Kb, contained ≥10 SNPs and had minimal overlap with CNVs from in-house controls, the Database of Genomic Variants, HapMap3, and Childrens Hospital of Philadelphia database.
We identified 28 CNVs in 17 cases; several encompassed genes important for right heart development. One case had a 2p16-2p23 duplication spanning LBH, a limb and heart development transcription factor. Lbh mis-expression results in right ventricular hypoplasia and pulmonary valve defects. This duplication also encompassed SOS1, a factor associated with pulmonary valve stenosis in Noonan syndrome. Sos1 mice display thin and poorly trabeculated ventricles. In another case, we identified a 1.5 Mb deletion associated with Williams-Beuren syndrome, a disorder that includes valvular malformations. A third case had a 24 Kb deletion upstream of the TGFβ ligand ITGB8. Embryos genetically null for Itgb8, and its intracellular interactant Band 4.1B, display lethal cardiac phenotypes.
To our knowledge, this is the first study of CNVs in HRHS. We identified several rare CNVs that overlap genes related to right ventricular wall and valve development, suggesting that genetics plays a role in HRHS and providing clues for further investigation. Birth Defects Research 109:16-26, 2017. © 2016 Wiley Periodicals, Inc.
右心发育不全综合征（HRHS）是一种罕见的先天性缺陷，其特征为右心结构发育不全，常伴有房间隔缺损。家族性 HRHS 报告提示存在遗传因素。我们研究了拷贝数变异（CNVs）在 HRHS 中的作用。
我们使用 Illumina HumanOmni2.5 微阵列对从纽约州所有活产儿（1998-2005 年）中确定的 32 例 HRHS 病例进行了基因分型。使用 PennCNV 对 CNVs 进行了调用，如果 CNV 大于 20kb，包含大于 10 个 SNP，并且与内部对照、基因组变异数据库、HapMap3 和费城儿童医院数据库中的 CNVs 最小重叠，则将其视为优先考虑。
我们在 17 例病例中发现了 28 个 CNVs；其中几个包含对右心发育很重要的基因。一个病例存在 2p16-2p23 重复，跨越 LBH，这是一个肢体和心脏发育转录因子。Lbh 表达异常导致右心室发育不良和肺动脉瓣缺陷。该重复还包含 SOS1，一种与 Noonan 综合征相关的肺动脉瓣狭窄的因子。Sos1 小鼠表现出心室壁薄且小梁排列不良。在另一个病例中，我们发现了一个与威廉姆斯-贝伦综合征相关的 1.5Mb 缺失，该疾病包括瓣膜畸形。第三个病例存在 TGFβ 配体 ITGB8 上游的 24kb 缺失。Itgb8 及其细胞内相互作用蛋白 Band 4.1B 基因缺失的胚胎表现出致命的心脏表型。
据我们所知，这是 HRHS 中首次研究 CNVs。我们发现了几个罕见的 CNVs，这些 CNVs 与右心室壁和瓣膜发育相关的基因重叠，提示遗传在 HRHS 中起作用，并为进一步研究提供了线索。出生缺陷研究 109：16-26，2017。© 2016 Wiley Periodicals, Inc.
