Division of Intramural Population Health Research, Department of Health and Human Services, 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.
Am J Med Genet A. 2018 Dec;176(12):2760-2767. doi: 10.1002/ajmg.a.40527. Epub 2018 Oct 5.
Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdeveloped and malformed structures of the right heart. Familial recurrence of HRHS indicates genetic factors contribute to its etiology. Our study investigates the presence of copy number variants (CNVs) in HRHS cases. We genotyped 42 HRHS cases identified from live births throughout California (2003-2010) using the Illumina HumanOmni2.5-8 array. We identified 14 candidate CNVs in 14 HRHS cases (33%) based on the genes included in the CNVs and their functions. Duplications overlapping part of ERBB4 were identified in two unrelated cases. ERBB4 is a neuregulin receptor with a pivotal role in cardiomyocyte differentiation and heart development. We also described a 7.5 Mb duplication at 16q11-12. Multiple genes in the duplicated region have previously been linked to heart defects and cardiac development, including RPGRIP1L, RBL2, SALL1, and MYLK3. Of the 14 validated CNVs, we identified four CNVs in close proximity to genes linked to the Wnt signaling pathway. This study expands on our previous work supporting the role of genetics in HRHS. We identified CNVs affecting crucial genes and signaling pathways involved in right heart development. ERBB4 and duplication of the 16q11-12 region are important areas for future investigation.
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良和畸形。HRHS 的家族性复发表明遗传因素对其病因有影响。我们的研究调查了 HRHS 病例中拷贝数变异（CNVs）的存在。我们使用 Illumina HumanOmni2.5-8 阵列对加利福尼亚州（2003-2010 年）活产儿中确定的 42 例 HRHS 病例进行了基因分型。根据 CNVs 中包含的基因及其功能，我们在 14 例 HRHS 病例（33%）中确定了 14 个候选 CNVs。在两个无关联的病例中发现了 ERBB4 部分重叠的重复。ERBB4 是一种神经调节素受体，在心肌细胞分化和心脏发育中起着关键作用。我们还描述了 16q11-12 处的 7.5 Mb 重复。该重复区域中的多个基因以前与心脏缺陷和心脏发育有关，包括 RPGRIP1L、RBL2、SALL1 和 MYLK3。在 14 个经过验证的 CNVs 中，我们发现了 4 个与 Wnt 信号通路相关基因紧密相邻的 CNVs。这项研究扩展了我们之前的工作，支持遗传在 HRHS 中的作用。我们确定了影响右心发育的关键基因和信号通路的 CNVs。ERBB4 和 16q11-12 区域的重复是未来研究的重要领域。
