Open AccessPrenatal whole exome sequencing detects a new homozygous fukutin (FKTN) mutation in a fetus with an ultrasound suspicion of familial Dandy–Walker malformation
Author(s) -
Traversa Alice,
Bernardo Silvia,
Paiardini Alessandro,
Giovannetti Agnese,
Marchionni Enrica,
Genovesi Maria Luce,
Guadagnolo Daniele,
Torres Barbara,
Paolacci Stefano,
Bernardini Laura,
Mazza Tommaso,
Carella Massimo,
Caputo Viviana,
Pizzuti Antonio
Publication year - 2020
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1054
Subject(s) - missense mutation , exome sequencing , prenatal diagnosis , genetics , exome , ventriculomegaly , biology , comparative genomic hybridization , fetus , medicine , mutation , pathology , bioinformatics , gene , pregnancy , chromosome
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.