ESPE Abstracts

Background: Linear growth is a multifactorial trait.Short children in whom no definite etiology is found after thorough evaluation are considered to have idiopathic short stature (ISS). A proportion of these children have a monogenic basis of short stature.

Aim: To study the prevalence of mutations or pathogenic variants in SHOX, GHR and IGFALS genes among Indian children with ISS.

Methods: Children aged 4–16 years, with height below −2 SDS, who were born appropriate for gestational age (AGA) and in whom step-wise investigative work-up (including stimulated GH test) was normal, were recruited (n=61). Multiplex ligation-dependent probe amplification (MLPA), and direct sequencing were undertaken for identification of deletion/duplication and point mutations in SHOX gene. Bidirectional sequencing was performed for identification of mutations or likely pathogenic variants in GHR and IGFALS genes. IGFALS gene was sequenced only in children with fasting serum IGF1 below −1 SDS.

Results: Four children (6.5%) had mutations in SHOX gene. One had duplication of exon 5, the second had heterozygous splice site point mutation c.278-1G>C at acceptor site of exon 3, and one child each had partial and complete heterozygous deletion of SHOX gene. Height was worst affected in the children with the splice site point mutation c.278-1G>C, and complete delection (height SDS of −3.9 and −3.8, respectively), while it was much less affected in the children with duplication of exon 5 and partial deletion (height SDS of −2.4 and −2.1, respectively). None of the patients had mutation in GHR gene, although 7 non-pathogenic polymorphisms were observed. Out of 39 patients in whom IGFALS gene was sequenced, heterozygous frameshift or missense variants were found in 3 (7.8%) patients. One patient (height SDS −3.8) had a novel heterozygous frameshift variant (c.764_765insT, p.A265Gfs*114), which was predicted as disease causing variant by MutationTaster software. One patient (height −3.1 SDS) had heterozygous missense variant c.1756C>T, R586W in exon 2, which is a reported pathogenic variant. The third patient (height SDS −3.3) had heterozygous missense variant c.1793G>A, p.R598H in exon 2 which was predicted by Polyphen and MutationTaster softwares as possibly damaging and disease causing, respectively. The variants c.764_765insT, p.A265Gfs*114 and c.1756C>T, R586W were not found in a large normative data repository of Indian patients (MedGeneome Labs Pvt Ltd. Bangalore, India).

Conclusion: Mutations/ pathogenic variants in SHOX and IGFALS genes account for about 15% of ISS in Indian children.