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

Alice Traversa, Silvia Bernardo, Alessandro Paiardini, Agnese Giovannetti, Enrica Marchionni, Maria Luce Genovesi, Daniele Guadagnolo, Barbara Torres, Stefano Paolacci, Laura Bernardini, Tommaso Mazza, Massimo Carella, Viviana Caputo, Antonio Pizzuti

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numbere1054
JournalMolecular Genetics and Genomic Medicine
Publication statusAccepted/In press - Jan 1 2019


  • Dandy–Walker malformation
  • fetal imaging
  • FKTN
  • muscular dystrophy-dystroglycanopathy type A4
  • prenatal diagnosis
  • whole exome sequencing

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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