Molecular diagnosis of rare biallelic CDC45 gene variants causing Meier-Gorlin syndrome-7 using whole exome sequencing.

backgroundMeier–Gorlin syndrome-7 (MGORS7) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in the CDC45 gene. This study aims to present two rare CDC45 gene variants and a familial 13q31.1q31.3 microduplication in a fetus with multiple ultrasound anomalies.

methodsA fetus with multiple ultrasound anomalies including craniosynostosis, microtia, brachydactyly of left thumb, congenital heart defect, and other anomalies was recruited for genetic analysis. Chromosomal microarray analysis (CMA) and qPCR was used to detect copy number variants (CNVs). Whole exome sequencing (WES) was carried out to investigate the possible molecular cause. mRNA splicing analysis was used to reveal the molecular pathogenesis of the synonymous variant.

resultsA 2.6 Mb microduplication in the 13q31.1q31.3 region was identified in the fetus using CMA, which was inherited from the father who had normal clinical features. WES results demonstrated two compound heterozygous variants of NM_001178010.2: c.[1512 C > T]; [326_329dup] in the CDC45 gene in the fetus, which were inherited from the parents, respectively. Additionally, the subsequent mRNA splicing analysis indicated that the c.1512 C > T(p.H504=) synonymous variant in CDC45 may affect mRNA splicing but failed to complete Sanger sequencing verification.

conclusionOur findings first describe a more severe irregular skull of acrocephaly in a fetus with MGORS7, which may provide additional insights in genetic counselling of MGORS7. The c.1512 C > T(p.H504=) synonymous variant in CDC45 may influence mRNA splicing but needs more evidence.