Rare Copy Number Variants Are a Common Cause of Short Stature

Human growth has an estimated heritability of about 80%–90%. Nevertheless, the underlying cause of shortness of stature remains unknown in the majority of individuals. Genome-wide association studies (GWAS) showed that both common single nucleotide polymorphisms and copy number variants (CNVs) contribute to height variation under a polygenic model, although explaining only a small fraction of overall genetic variability in the general population. Under the hypothesis that severe forms of growth retardation might also be caused by major gene effects, we searched for rare CNVs in 200 families, 92 sporadic and 108 familial, with idiopathic short stature compared to 820 control individuals. Although similar in number, patients had overall significantly larger CNVs (p-value−7). In a gene-based analysis of all non-polymorphic CNVs>50 kb for gene function, tissue expression, and murine knock-out phenotypes, we identified 10 duplications and 10 deletions ranging in size from 109 kb to 14 Mb, of which 7 were de novo (p人类身高的遗传力估计约为80%~90%。然而，绝大多数身材矮小个体的潜在病因仍不明确。全基因组关联研究（Genome-Wide Association Studies, GWAS）表明，在多基因模型框架下，常见单核苷酸多态性与拷贝数变异（Copy Number Variants, CNVs）均会对身高变异产生贡献，但仅能解释普通人群中一小部分整体遗传变异。基于"严重生长迟缓或可由主要基因效应引发"这一假说，我们针对200个特发性身材矮小（idiopathic short stature, ISS）家系（含92个散发病例家系与108个家族性家系），并以820名对照个体作为参照，开展了罕见CNVs筛查。尽管两组的CNV数量相近，但患者组的CNV整体尺寸显著更大（p值<10^-7）。在针对所有长度大于50kb的非多态性CNVs开展的基于基因功能、组织表达特征及小鼠敲除表型的基因水平分析中，我们共鉴定出10个重复变异与10个缺失变异，变异区间跨度为109kb至14Mb，其中7个为新发（de novo）变异（p