Evaluation of the genotype-phenotype correlation by using the whole exome sequencing of possible candidate genes in pediatric cases with non-syndromic craniosynostosis

Objective: Non-syndromic craniosynostosis is a congenital malformation caused by the premature suture fusion. In this project, we aimed to brighten the genotype-phenotype correlations of the non-syndromic craniosynostosis by using targetted exome sequencing. Method: 30 non-syndromic cases with wild genotype for FGFR2 exon IIIa and IIIc, and normal karyotype were included in the study. Twenty-one of the cases were sequenced by using next-generation targeted exome sequencing of the research panel including 519 genes. The other nine of the cases were analyzed by using Sanger sequencing for the exons carried possibly pathogenic mutations which were identified in twenty-one of the cases. The obtained molecular genetic data were compared with the clinical data of the cases and the genotype-phenotype correlation was evaluated. Results: As a result of the clinical evaluation, 37% of the cases have sagittal synostosis and followed by coronal, metopic and multisuture synostosis with 33%, 20%, and 10%, respectively. Besides, it has been determined that 47% of the cases have at least one ocular abnormality. As a result of DNA sequencing, it has been detected that 20% of the cases have pathogenic mutations in AXIN2, TCF12 and ERF genes. It has been seen that cases with p.M260fs*5 and p.P369fs*26 mutations in TCF12 gene have coronal synostosis, the case with p.L349fs*24 mutation in AXIN2 gene has sagittal synostosis and the case with p.G299fs*9 mutation in ERF gene has unilateral coronal synostosis and closed fontanelles. In addition to these, by using Sanger sequencing, c.825+5G>T splice region mutation in TCF12 gene was detected in a case with brachycephaly. Conclusion: Non-syndromic craniosynostosis is both genotypically and phenotypically heterogeneous anomaly. Our findings revealed that screening of the genes depending on the type of closed suture in non-syndromic craniosynostosis cases may lead to a faster genetic diagnosis. Key words: craniosynostosis, next generation sequencing, molecular genetics, nonsyndromic craniosynostosis, genetic