Genetic Evaluation of Idiopathic Short Stature

Abstract

Introduction: Short stature is a multifactorial condition causedby both genetic and environmental factors. Genetic causes includechromosomal disorders and diseases inherited by monogenic andmultifactorial inheritance. The purpose of genetic evaluation inshort stature is not only for diagnosis, but also to provide additionalinformation to the patients and their families about prognosis ofthe disease, treatment approaches and genetic counseling.Aim: This study aims to investigate genetic etiology by usingcytogenetic, molecular cytogenetic and next generation sequencingmethods in patients with idiopathic short stature.Patients and Method: In this study, 189 patients, inwhom chronic diseases, hormonal disorders and skeletal dysplasiawere excluded, and diagnosed as idiopathic short stature wereincluded in the study. We did an algorithmic approach for geneticscreening.In the first phase cytogenetic investigations were doneand chromosomal anomalies were excluded. Then SHOX gene deletionswere investigated by fluorescent in situ hybridization andpossible submicroscopic deletions and duplications by a-CGHtechnique. After these evaluation 41patients, found to have normalchromosomal segments, underwent to next generation sequencingof the Ion Torrent platform with 25 gene-containing panelgenetests. Gene panel consisted of 10 genes associated with shortstature (GH1,GHR,GHRH GHSR, IGF1,IGF1R,IGFALS,IGFBP3,SHOX,STAT5B) and 15 genes (POU1F1,PROP1,HESX1,LHX3,LHX4,IGSF1,OTX2,BMP4,SHH,WDR11,FGFR1,FGF8,PROKR2,SOX3,HHIP)associated with isolated or multiple pituitary hormonedeficiency(MPHD)Results: Of the 189 patients with short stature, 16(8.5%) hadchromosomal anomaly,1 had microdeletion in the SHOX genewith FISH examination, and 1 patient had a deletion of 2.7MBin the 5q32 region with a-CGH assay. In five patients, 5 differentvariations were detected (BMP4,GHR, IGSF1, LHX4 and-PROKR2) (one in short stature genes, 4 in MPHD genes). One ofthis mutations was novel, one of them was previously defined and3 of them were found in databases. The changes that were thoughtto be of clinical importance were confirmed by Sanger sequencingmethod. It was shown that 4 heterozygous changes found in thesegregation analysis were also found in the healthy individuals inthe family and in one patient with homozygous change, the parentswere shown to be heterozygous carriers.Conclusion: Short stature for gene panel test was first evaluatedin Turkey. We recommend cytogenetic examination beforemolecular analysis to exclude chromosomal anomalies and microdeletions.Because short stature has a wide genetic spectrum, wethink that the targeted panels are not sufficient. We propose wholeexom or whole genome sequencing analysis with a healthy controlgroup and the index patients and parents.