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Genetic studies of 77 cases of short stature with unknown etiology

??Objective??To detect pathogenic genes of short stature with unknown etiology by a targeted next generation sequencing panel to analyze the correlation between genotypes and clinical phenotypes. Methods??A total of 77 children diagnosed with unexplained short stature were enrolled for the study. These children were treated in Ruijin Hospital of Shanghai Jiao Tong University from 2007 to 2015. To search for genetic variation in 187 candidate genes which were associated with growth?? we constructed a targeted next generation sequencing panel encompassing the coding regions of 187 genes. According to ACMG Guidelines??the sites of variation were determined. Sanger sequencing was used to verify the suspected pathogenic genes variation. The relationship between genotype and clinical phenotype was analyzed. Results??Including 5 pathogenic variants?? one likely pathogenic variant and one variant of uncertain significance?? we identified 7 heterozygous variants of 7 cases in 77 cases of short stature with unknown etiology. A pathogenic variant p.D2407fs of ACAN gene was found in a case with advanced bone age. There were 3 reported pathogenic variants?? including p.A72G?? p.I282V and p.P491S of PTPN11 gene?? which were diagnosed as Noonan syndrome. A case carrying known pathogenic variant COL2A1??p.R904C?? was diagnosed as Stickler syndrome. We still got one likely pathogenic variant COMP??p.D401N???? which could cause multiple epiphyseal dysplasia. There was a familial short stature of delayed bone age carrying a variant??p.S289Y?? of uncertain significance??in which the genotype was in accordance with the clinical phenotype. Conclusion??The ACAN gene defection is associated with the idiopathic short stature with advanced bone age. The likely pathogenic variant COMP??p.D401N?? may cause multiple epiphyseal dysplasia. The newly-found heterozygous varians??p.S289Y?? of GHSR gene may result in short stature??which needs further function verification.