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Licensed Unlicensed Requires Authentication Published by De Gruyter December 13, 2019

Pathogenic/likely pathogenic variants in the SHOX, GHR and IGFALS genes among Indian children with idiopathic short stature

Anil Kumar, Vandana Jain, Madhumita Roy Chowdhury, Manoj Kumar, Punit Kaur and Madhulika Kabra



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.


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.


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.


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.

Corresponding author: Prof. Dr. Vandana Jain, Division of Pediatric Endocrinology, Department of Pediatrics, All India Institute of Medical Sciences, Room No. 3063, Teaching Block, New Delhi, India, Phone: +91-11-26594345


We thank all the patients and their family members for their participation in this study, Mr. Brijesh for performing ECLIA for GH assay and Dr. Ankita Pal for help with enrollment of the patients. This work was supported by research grants to VJ from the All India Institute of Medical Sciences, New Delhi [grant number F.8-169/A-169/2012/RS and F.8-389/A-389/2015/RS] and to AK from the Indian Council of Medical Research, New Delhi [grant number 3/1/3/JRF-2011/HRD 45 (34683)].

  1. Author contributions: AK was involved in conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology and writing the original draft of the paper; VJ conceived and supervised the study, critically revised the paper and will act as guarantor; MRC and MK supervised the molecular work; and MK and PK supervised the molecular. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of report; or in the decision to submit the report for publication.


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Supplementary Material

The online version of this article offers supplementary material (

Received: 2019-05-25
Accepted: 2019-10-13
Published Online: 2019-12-13
Published in Print: 2020-01-28

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