Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature
Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature
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DOI：
10.1507/endocrj.ej17-0150
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发表时间：
2017-01-01
影响因子：
2
通讯作者：
Fukami, Maki
中科院分区：
文献类型：
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作者：
Hattori, Atsushi;Katoh-Fukui, Yuko;Fukami, Maki
尽管ACAN、FGFR 3、NPR 2和SHOX的突变通常导致骨骼发育不良，而GHRHR、GH 1、GHR、STAT 5 B、IGF 1、IGFALS和IGF 1 R的突变通常是生长激素（GH）胰岛素样生长因子1（IGF 1）轴激素缺陷的基础，但在特发性身材矮小（ISS）患者中也发现了此类突变。其中，已知SHOX异常占ISS病例的一定比例，而ISS队列中其他10个基因的突变频率仍然未知。在这里，我们对86名无SHOX异常的无关日本ISS患者的10个基因进行了下一代基于测序的突变筛查。我们寻找罕见的蛋白质改变变体。通过计算机模拟分析评估所鉴定变体的功能意义。因此，我们在19名患者中鉴定了18种杂合罕见变异，包括4种可能的ACAN损伤性变异，6种致病性未知的FGFR 3、GHRHR、GHR和IGFALS变异，以及8种可能的良性变异。我们的队列中不存在NPR 2、GH 1和IGF 1的致病性变体。与先前报道的ACAN突变患者不同，我们的4例ACAN变异患者表现为非特异性身材矮小，骨龄与年龄相适应或轻度延迟，父母身高正常。这些结果表明，ACAN基因突变可能是ISS的基础，没有特征性的骨骼特征，这种突变可能与从头发生或低发病率。此外，我们的数据表明FGFR 3、NPR 2和GH-IGF 1轴基因突变在ISS的病因学中仅起有限的作用。
Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.