Glidewell Steven C, Miyamoto Shelley D, Grossfeld Paul D, Clouthier David E, Coldren Christopher D, Stearman Robert S, Geraci Mark W
Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Clin Transl Sci. 2015 Dec;8(6):682-9. doi: 10.1111/cts.12340. Epub 2015 Nov 4.
Hypoplastic left heart syndrome (HLHS) is a heterogeneous, lethal combination of congenital malformations characterized by severe underdevelopment of left heart structures, resulting in a univentricular circulation. The genetic determinants of this disorder are largely unknown. Evidence of copy number variants (CNVs) contributing to the genetic etiology of HLHS and other congenital heart defects has been mounting. However, the functional effects of such CNVs have not been examined, particularly in cases where the variant of interest is found in only a single patient.
Whole-genome SNP microarrays were employed to detect CNVs in two patient cohorts (N = 70 total) predominantly diagnosed with some form of nonsyndromic HLHS. We discovered 16 rare or private variants adjacent to or overlapping 20 genes associated with cardiovascular or premature lethality phenotypes in mouse knockout models. We evaluated the impact of selected variants on the expression of nine of these genes through quantitative PCR on cDNA derived from patient heart tissue. Four genes displayed significantly altered expression in patients with an overlapping or proximal CNV verses patients without such CNVs.
Rare and private genomic imbalances perturb transcription of genes that potentially affect cardiogenesis in a subset of nonsyndromic HLHS patients.
左心发育不全综合征（HLHS）是一种先天性畸形的异质性致死组合，其特征为左心结构严重发育不全，导致单心室循环。该疾病的遗传决定因素在很大程度上尚不清楚。拷贝数变异（CNV）导致HLHS及其他先天性心脏缺陷的遗传病因的证据越来越多。然而，此类CNV的功能效应尚未得到研究，尤其是在仅在一名患者中发现感兴趣变异的情况下。
采用全基因组SNP微阵列检测两个患者队列（共70例）中的CNV，这些患者主要被诊断为某种形式的非综合征性HLHS。我们在小鼠基因敲除模型中发现了16个与心血管或过早致死表型相关的20个基因相邻或重叠的罕见或私有变异。我们通过对来自患者心脏组织的cDNA进行定量PCR，评估了所选变异对其中9个基因表达的影响。在有重叠或近端CNV的患者与无此类CNV的患者中，有4个基因的表达显示出显著改变。
罕见和私有基因组失衡扰乱了非综合征性HLHS患者亚组中可能影响心脏发生的基因转录。
