Rare CNVs provide novel insights into the molecular basis of GH and IGF-1 insensitivity.
Rare CNVs provide novel insights into the molecular basis of GH and IGF-1 insensitivity.
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DOI：
10.1530/eje-20-0474
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发表时间：
2020-12
影响因子：
5.8
通讯作者：
Storr HL
中科院分区：
文献类型：
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作者：
Cottrell E;Cabrera CP;Ishida M;Chatterjee S;Greening J;Wright N;Bossowski A;Dunkel L;Deeb A;Basiri IA;Rose SJ;Mason A;Bint S;Ahn JW;Hwa V;Metherell LA;Moore GE;Storr HL
拷贝数变异（CNV）与特发性身材矮小、胎龄小和银罗素综合征（SRS）有关。在生长激素不敏感（GHI，身材矮小，IGF-1缺乏和正常/高生长激素）或IGF-1不敏感（身材矮小，高/正常生长激素和IGF-1）中尚未广泛研究。采用~ 60000探针寡核苷酸阵列对53例GHI和10例IGF-1不敏感患者进行比较基因组杂交。利用已发表的文献、小鼠模型、破译CNV轨迹、生长相关的GWAS位点和途径富集分析来确定CNV区域内的关键生物学途径/新的候选生长基因。两个队列都富集了3-5类CNVs (7/53 （13%) GHI和3/10 (30%)IGF-1不敏感患者）。有趣的是，6/10（60%）的CNV受试者具有SRS的诊断/相关临床特征。5/10受试者（50%）先前报告的疑似SRS中存在CNVs: 1q21 （n = 2）、12q14 （n = 1）缺失和Xp22 （n = 1）、Xq26 （n = 1）重复。发现了一种新的15q11缺失，以前与生长衰竭有关，但与SRS/GHI无关。生物信息学分析鉴定出45个新的候选生长基因，其中15个与GWAS的生长有关。WNT典型通路在GHI组中丰富，CLOCK在IGF-1不敏感组中被确定为上游调节因子。我们的队列丰富了低频CNVs。我们的研究强调了对GHI和IGF-1不敏感患者，特别是具有SRS特征的GHI患者进行CNV检测的重要性。现在需要功能性实验证据来验证新的候选生长基因、相互作用和确定的生物学途径。
Copy number variation (CNV) has been associated with idiopathic short stature, small for gestational age and Silver-Russell syndrome (SRS). It has not been extensively investigated in growth hormone insensitivity (GHI; short stature, IGF-1 deficiency and normal/high GH) or previously in IGF-1 insensitivity (short stature, high/normal GH and IGF-1). Array comparative genomic hybridisation was performed with ~60 000 probe oligonucleotide array in GHI (n = 53) and IGF-1 insensitivity (n = 10) subjects. Published literature, mouse models, DECIPHER CNV tracks, growth associated GWAS loci and pathway enrichment analyses were used to identify key biological pathways/novel candidate growth genes within the CNV regions. Both cohorts were enriched for class 3–5 CNVs (7/53 (13%) GHI and 3/10 (30%) IGF-1 insensitivity patients). Interestingly, 6/10 (60%) CNV subjects had diagnostic/associated clinical features of SRS. 5/10 subjects (50%) had CNVs previously reported in suspected SRS: 1q21 (n = 2), 12q14 (n = 1) deletions and Xp22 (n = 1), Xq26 (n = 1) duplications. A novel 15q11 deletion, previously associated with growth failure but not SRS/GHI was identified. Bioinformatic analysis identified 45 novel candidate growth genes, 15 being associated with growth in GWAS. The WNT canonical pathway was enriched in the GHI cohort and CLOCK was identified as an upstream regulator in the IGF-1 insensitivity cohorts. Our cohort was enriched for low frequency CNVs. Our study emphasises the importance of CNV testing in GHI and IGF-1 insensitivity patients, particularly GHI subjects with SRS features. Functional experimental evidence is now required to validate the novel candidate growth genes, interactions and biological pathways identified.