Molecular Diagnostic Algorithm of Syndromic Craniosynostosis

Abstract

Craniosynostosis(CS) is a birth defect, with a prevalence of 1/2100-1/2500,caused by the premature fusion of one or more cranial sutures leading tospeci����ic cranial base and vault abnormalities. It is a highly heterogeneousgroup of disorders occurring both in syndromic and non-syndromic forms,associated with approximately 180 different syndromes. The identi����icationof the responsible gene largely depends on the fact if it is syndromicor non-syndromic. Although 85% of the cases are reported to be non-syndromicwith unknown etiology, syndromic forms arise from chromosomalanormalies or single gene defects of Mendelian inheritance, both togethercomprising the etiopathogenesis only in 40% of the cases and single genedefects contributing to three/fourth. Noteworthy genes in this group areFGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2, RAB23 and FREM1. EFNB1can be excluded from this group due to its association with CraniofrontonasalSyndrome. Thirty syndromic CS patients with normal karyotype wereincluded in the study cohort. Stepwise screening algorithm was applied, initialstep being the sequencing of FGFR2, FGFR3 and FGFR1, followed by fullgene sequencing of FGFR2 and FGFR3. Samples with unidenti����ied etiologywere further screened for deletion/duplication by craniofrontonasal MLPAkit (P080). The last step consisted of sequencing of FGFR1, MSX2, TWIST1,RAB23 and FREM1 genes, when the cases showed distinct related clinicalphenotype.We highly suggest that our ongoing research will lead to better insight forthe clinical diagnosis, molecular diagnostic ����low charts in CS and will contributeto the genotype-phenotype correlation.