Prenatal whole exome sequencing detects a new homozygous fukutin (FKTN) mutation in a fetus with an ultrasound suspicion of familial Dandy-Walker malformation.

ABSTRACT: BACKGROUND:Posterior fossa malformations are among the most diagnosed central nervous system (CNS) anomalies detected by ultrasound (US) in prenatal age. We identified the pathogenic gene mutation in a male fetus of 17 weeks of gestation with US suspicion of familial Dandy-Walker spectrum malformation, using Next Generation Sequencing approach in prenatal diagnosis. METHODS:Whole exome sequencing (WES) approach has been performed on fetal genomic DNA. After reads preprocessing, mapping, variant calling, and annotation, a filtering strategy based on allelic frequency, recessive inheritance, and phenotypic ontologies has been applied. A fetal magnetic resonance imaging (MRI) at 18 weeks of gestation has been performed. An in silico analysis of a potential causative missense variant in the fukutin protein has been carried out through a structural modeling approach. RESULTS:We identified a new homozygous missense mutation in fukutin gene (FKTN, NM_006731.2: c.898G>A; NP_006722.2: p.Gly300Arg). Fetal MRI supported molecular findings. Structural modeling analyses indicated a potential pathogenetic mechanism of the variant, through a reduced activation of the sugar moieties, which in turn impairs transfer to dystroglycan and thus its glycosylation. These findings pointed to a redefinition of the US suspicion of recurrence of Dandy-Walker malformation (DWM) to a muscular dystrophy-dystroglycanopathy type A4. CONCLUSIONS:The present case confirmed WES as a reliable tool for the prenatal identification of the molecular bases of early-detected CNS malformations.

SUBMITTER: Traversa A 

PROVIDER: S-EPMC6978243 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature