The Correlational Studies On Pathogenic Genes In Short Stature Of Unknown Etiology

Objects:Short stature is a common pediatric endocrine disease,the incidence rate is about3~5%,which is part of the known causes.However,the majority of patients presenting with short stature do not receive a definitive diagnosis.For this unknown etiology,recombinant human growth hormone maybe the main treatment regimen,but due to the heterogeneity of pathological mechanism,the effects are not assured.It not only increases health-care costs and the financial burden to families and societies but also has a negative impact on children's psychology.With the development of molecular technology and genetic sequencing,it is possible to clarify the molecular etiology.In order to clarify the genetic characteristics of these patients and provide scientific basis for clinical diagnosis and treatment,this study was to screen for pathogenic genes in short stature of unknown etiology,by using the technique of targeted next generation sequencing.Subjects and Methods :Exclusion of known etiologies,such as growth hormone deficiency,small for gestational age,hypothyroidism,chromosomal abnormalities,obvious skeletal abnormalities,and other acquired short stature;a total of 81 subjects diagnosed as short stature of unknown etiology were enrolled.Genomic DNA from patients' peripheral blood leukocytes was obtained.Developing a targeted next generation sequencing panel encompassing the exonic coden regions of 187 genes involving growth relevant pathway,81 cases were sequenced by this panel.The traditional Sanger sequencing was used to verify the suspected pathogenic variants.And combined with clinical data,analyze the correlation between gene variation and clinical phenotype.Results:We identified 10 genetic variants of 11 cases in 81 short stature of unknown etiology.Of those,5 pathogenic variants and one likely pathogenic variant were found.In addition,the other 5 cases carrying variant of uncertain significance could need further function detection and clinical follow-up.A total of 5 cases were found to have heterozygous pathogenic variant,including ACAN: c.7222dupA:p.D2407fs(idiopathic short stature with advanced bone age),PTPN11:c.215C>G:p.A72 G and c.844A>G:p.I282 V and c.1471C>T:p.P491S(Noonan syndrome),COL2A1:c.2710C>T:p.R904C(Stickler syndrome).We still got a heterozygous likely pathogenic variant COMP:c.1201G>A:p.D401 N,which could cause multiple epiphyseal dysplasia.And 4variants of uncertain significance,including COL10A1:c.1228G>C: p.G410R/het(2cases),GHSR:c.866C>A:p.S289Y/het,CENPJ:c.2462C>T:p.T821M/hom,COL1A1:c.1583G>A:p.R528H/het,were found in 5 cases diagnosed as short stature.Conclusions:1.The genetic variation of 11 patients were found in 81 unexplained short stature in patients(13.5%),of which 5 pathogenic variant and a likely pathogenic variant(7.4%),the other 5 cases carrying variant of uncertain significance,which need further functional verification testing and clinical follow-up.2.The ACAN gene is associated with the idiopathic short stature with advanced bone age,which enriches the gene variation spectrum of patients with idiopathic short stature.3.Atypical clinical features of some syndromes are always overlooked,and these are often classified as a type of obscure dwarf.Through this gene panel,3 cases of Noonan syndrome,and 1 case of Stickler syndrome were confirmed,which provided scientific basis for clinical treatment.4.The likely pathogenic variant COMP:c.1201G>A:p.D401 N maybe cause multiple epiphyseal dysplasia.5.This gene panel has the potential to rapidly identify genetic etiologies of short stature, and provide scientific basis for the clinical management.