Kumar Anil, Jain Vandana, Chowdhury Madhumita Roy, Kumar Manoj, Kaur Punit, Kabra Madhulika
Division of Pediatric Endocrinology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
J Pediatr Endocrinol Metab. 2020 Jan 28;33(1):79-88. doi: 10.1515/jpem-2019-0234.
Background Our objective was to estimate the prevalence of pathogenic/likely pathogenic variants in the SHOX, GHR, and IGFALS genes among Indian children with idiopathic short stature (ISS), and assess the genotype-phenotype correlation. Methods We recruited 61 children with short stature, who were born appropriate for gestational age, had no obvious dysmorphism or disproportion, and in whom step-wise investigative work-up (including provocative growth hormone test) was normal. Multiplex ligation-dependent probe amplification was undertaken for identifying deletions/duplications in the SHOX gene. Bidirectional sequencing was performed for identifying variants in the SHOX and GHR genes in all, and for the IGFALS gene in those with serum insulin-like growth factor-1 (IGF-1) <-1 standard deviation. The genotype-phenotype correlation was studied. Results Four children (6.5%) had pathogenic heterozygous variants in the SHOX gene, with one child each having duplication of exon 5, splice site point variant c.278-1G > C in exon 3, partial deletion and complete deletion. None of the patients had pathogenic variants in the GHR gene. Of the 39 patients in whom the IGFALS gene was sequenced, novel heterozygous likely pathogenic variants were found in two children. One had the frameshift variant c.764_765insT, p.A265Gfs*114. The second had the missense variant c.1793G > A, p.R598H predicted by MutationTaster as 'disease causing', and indicated by the protein-modelling study as having compromised binding with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) due to altered conformation of the interacting loop. Conclusions Pathogenic variants in the SHOX and IGFALS genes account for a significant proportion of Indian children with ISS. Further molecular studies using next generation sequencing are needed to gain insight into pathophysiological mechanisms and effective treatment strategies for ISS.
背景 我们的目的是估计印度特发性矮小（ISS）儿童中SHOX、GHR和IGFALS基因的致病/可能致病变异的患病率，并评估基因型与表型的相关性。方法 我们招募了61名身材矮小的儿童，他们出生时适于胎龄，无明显畸形或比例失调，且逐步的检查（包括生长激素激发试验）结果正常。采用多重连接依赖探针扩增技术鉴定SHOX基因的缺失/重复。对所有儿童进行SHOX和GHR基因的双向测序，对血清胰岛素样生长因子-1（IGF-1）<-1标准差的儿童进行IGFALS基因的双向测序。研究基因型与表型的相关性。结果 4名儿童（6.5%）在SHOX基因中有致病杂合变异，其中1名儿童外显子5重复，1名儿童外显子3剪接位点点变异c.278-1G>C，1名儿童部分缺失，1名儿童完全缺失。所有患者的GHR基因均无致病变异。在39名进行IGFALS基因测序的患者中，2名儿童发现了新的杂合可能致病变异。1名儿童有移码变异c.764_765insT，p.A265Gfs*114。另1名儿童有错义变异c.1793G>A，p.R598H，MutationTaster预测为“致病”，蛋白质建模研究表明由于相互作用环构象改变，该变异与IGF-1和胰岛素样生长因子结合蛋白-3（IGFBP-3）的结合受损。结论 SHOX和IGFALS基因的致病变异在印度ISS儿童中占相当比例。需要进一步使用下一代测序进行分子研究，以深入了解ISS的病理生理机制和有效治疗策略。
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