Novel Mutations and Genes That Impact on Growth in Short Stature of Undefined Aetiology: The EPIGROW Study.

ABSTRACT: Background:Children with short stature of undefined aetiology (SS-UA) may have undiagnosed genetic conditions. Purpose:To identify mutations causing short stature (SS) and genes related to SS, using candidate gene sequence data from the European EPIGROW study. Methods:First, we selected exonic single nucleotide polymorphisms (SNPs), in cases and not controls, with minor allele frequency (MAF)??2%, genotype present in?>?75%, and Hardy Weinberg equilibrium P?>?10-4. Results:First, a diagnostic yield of 10% (27/263) was generated by 2 pathogenic (nonsense in ACAN) and a further 25 likely pathogenic mutations, including previously known missense mutations in FANCB, IGFIR, MMP13, NPR2, OBSL1, and PTPN11. Second, genes related to SS: all methods identified PEX2. Another 7 genes (BUB1B, FANCM, CUL7, FANCA, PTCH1, TEAD3, BCAS3) were identified by both gene-based approaches and 6 (A2M, EFEMP1, PRKCH, SOS2, RNF135, ZBTB38) were identified by gene-based testing for all SNPs and PLINK. Conclusions:Such panels improve diagnosis in SS-UA, extending known disease phenotypes. Fourteen genes related to SS included some known to cause growth disorders as well as novel targets.

SUBMITTER: Perchard R 

PROVIDER: S-EPMC7482646 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature