Rare copy number variants are a common cause of short stature.
Rare copy number variants are a common cause of short stature.
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DOI：
10.1371/journal.pgen.1003365
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Thiel CT
中科院分区：
文献类型：
--
作者：
Zahnleiter D;Uebe S;Ekici AB;Hoyer J;Wiesener A;Wieczorek D;Kunstmann E;Reis A;Doerr HG;Rauch A;Thiel CT
据估计，人类生长的遗传率约为80%-90%。然而，大多数人身材矮小的根本原因仍不清楚。全基因组关联研究（GWAS）表明，在多基因模型下，常见的单核苷酸多态性和拷贝数变异（CNVs）都有助于身高变化，尽管它们只能解释普通人群中总体遗传变异的一小部分。假设严重形式的生长迟缓也可能由主要基因作用引起，我们在200个家族中寻找罕见的CNVs，其中92个是散发性的，108个是家族性的，与820个对照个体相比，特发性身材矮小。虽然数量相似，但患者总体上的CNVs明显较大（p值<1×10−7）。在对所有bb0 50kb的非多态性CNVs进行基因功能、组织表达和小鼠敲除表型的基因分析中，我们发现了10个重复和10个缺失，大小从109 kb到14 Mb不等，其中7个是从头开始（p<0.03）， 13个遗传自同样受影响的亲本，但在对照组中没有。这些可能导致20个CNVs的疾病的患者少于其余组（p<0.01）。这些cnv中有11个（55%）与已知的与身材矮小相关的微畸变综合征重叠，或包含与身高相关的GWAS位点。单倍不全（HI）评分和进一步的表达谱分析表明，这些位点上的主要生长相关基因对剂量敏感。总体而言，10%的患者携带致病的CNV，这表明，与神经发育障碍一样，罕见的CNV是严重生长迟缓的常见原因。身材矮小是一种常见的医学问题，发病率为3%。尽管家庭研究清楚地表明，基因缺陷在身材矮小的发展中起着关键作用，但在大约80%的病例中，潜在的遗传变异仍然未知。最近的研究旨在识别常见的遗传变异，以解释一般人群中身高变化的微小差异，与此相反，我们瞄准了罕见的基因组变异，我们预计这些变异会对生长产生主要的基因影响。通过检查200例临床评估为身材矮小的患者，我们发现10%的病例中罕见的结构性染色体畸变（CNVs）与身材矮小有关。鉴定出的CNVs要么是从头开始的，要么是在家族中分离出身材矮小的，包括在功能上参与人类或小鼠生长调节的基因。我们进一步证明了这些CNVs与已知的微缺失综合征的重叠。有趣的是，3个cnv包含常见变异的位置，并证实了主要生长相关基因的定位。这些发现对于确定导致身材矮小的生物学途径以及进一步的治疗方法尤其重要。
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<1×10−7). 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<0.03) and 13 inherited from the likewise affected parent but absent in controls. Patients with these likely disease causing 20 CNVs were smaller than the remaining group (p<0.01). Eleven (55%) of these CNVs either overlapped with known microaberration syndromes associated with short stature or contained GWAS loci for height. Haploinsufficiency (HI) score and further expression profiling suggested dosage sensitivity of major growth-related genes at these loci. Overall 10% of patients carried a disease-causing CNV indicating that, like in neurodevelopmental disorders, rare CNVs are a frequent cause of severe growth retardation. With a frequency of 3%, shortness of stature is a common medical concern. Although family studies have clearly shown that gene defects play a pivotal role in the development of short stature, the underlying genetic variants involved remain unknown in about 80% of cases. In contrast to recent studies which aimed at the identification of common genetic variants to explain minor differences in the height variation in the general population, we targeted rare genomic variants where we expected a major gene effect on growth. By examining 200 patients clinically evaluated for short stature, we show that rare structural chromosomal aberrations (CNVs) are associated with shortness of stature in 10% of the cases. The identified CNVs were either de novo or segregated with short stature in the families and include genes that are functionally involved in growth regulation in humans or mice. We furthermore demonstrate an overlap of these CNVs with known microdeletion syndromes. Interestingly, 3 CNVs contain positions of common variants and confirm the localization of major growth-related genes. These findings are particularly important for identification of biological pathways leading to short stature, but also for further therapeutic approaches.
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DOI：
10.1097/gim.0b013e3181a7e8f8
发表时间：
2009-06
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Seaver LH;Irons M;American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee
通讯作者：
American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee
影响因子：
8.8
作者：
Digilio, MC;Marino, B;Dallapiccola, B
通讯作者：
Dallapiccola, B
DOI：
10.1007/bf02310972
发表时间：
1981-01-01
期刊：
KLINISCHE WOCHENSCHRIFT
影响因子：
--
作者：
PRADER, A
通讯作者：
PRADER, A
影响因子：
9.8
作者：
Ben-Shachar, Shay;Ou, Zhishuo;Patel, Ankita
通讯作者：
Patel, Ankita
影响因子：
30.8
作者：
Sharp, Andrew J.;Hansen, Sierra;Eichler, Evan E.
通讯作者：
Eichler, Evan E.