Novel mutations and genes that impact on growth in short stature of undefined aetiology: the EPIGROW study

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.