Introduction: Short stature is a multifactorial condition caused by both genetic and environmental factors. Genetic causes include chromosomal disorders and diseases inherited by monogenic and multifactorial inheritance. The purpose of genetic evaluation in short stature is not only for diagnosis, but also to provide additional information to the patients and their families about prognosis of the disease, treatment approaches and genetic counseling.
Aim: This study aims to investigate genetic etiology by using cytogenetic, molecular cytogenetic and next generation sequencing methods in patients with idiopathic short stature.
Patients and Method: In this study, 189 patients, in whom chronic diseases, hormonal disorders and skeletal dysplasia were excluded, and diagnosed as idiopathic short stature were included in the study. We did an algorithmic approach for genetic screening.In the first phase cytogenetic investigations were done and chromosomal anomalies were excluded. Then SHOX gene deletions were investigated by fluorescent in situ hybridization and possible submicroscopic deletions and duplications by a-CGH technique. After these evaluation 41patients, found to have normal chromosomal segments, underwent to next generation sequencing of the Ion Torrent platform with 25 gene-containing panel-gene tests. Gene panel consisted of 10 genes associated with short stature (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 hormone deficiency(MPHD)
Results: Of the 189 patients with short stature, 16(8.5%) had chromosomal anomaly,1 had microdeletion in the SHOX gene with FISH examination, and 1 patient had a deletion of 2.7MB in the 5q32 region with a-CGH assay. In five patients, 5 different variations were detected (BMP4,GHR, IGSF1, LHX4 and PROKR2) (one in short stature genes, 4 in MPHD genes). One of this mutations was novel, one of them was previously defined and 3 of them were found in databases. The changes that were thought to be of clinical importance were confirmed by Sanger sequencing method. It was shown that 4 heterozygous changes found in the segregation analysis were also found in the healthy individuals in the family and in one patient with homozygous change, the parents were shown to be heterozygous carriers.
Conclusion: Short stature for gene panel test was first evaluated in Turkey. We recommend cytogenetic examination before molecular analysis to exclude chromosomal anomalies and microdeletions. Because short stature has a wide genetic spectrum, we think that the targeted panels are not sufficient. We propose whole exom or whole genome sequencing analysis with a healthy control group and the index patients and parents.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology