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.

Prenatal whole exome sequencing detects a new homozygous fukutin (FKTN) mutation in a fetus with an ultrasound suspicion of familial Dandy-Walker malformation / Traversa, A; Bernardo, S; Paiardini, A; Giovannetti, A; Marchionni, E; Genovesi, Ml; Guadagnolo, D; Torres, B; Paolacci, S; Bernardini, L; Mazza, T; Carella, M; Caputo, V; Pizzuti, A. - In: MOLECULAR GENETICS & GENOMIC MEDICINE. - ISSN 2324-9269. - (2019). [10.1002/mgg3.1054]

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

Traversa A
;
Paiardini A;Marchionni E;Genovesi ML;Guadagnolo D;Torres B;Caputo V;Pizzuti A
2019

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.
Dandy-Walker malformation; FKTN; fetal imaging; muscular dystrophy-dystroglycanopathy type A4; prenatal diagnosis; whole exome sequencing
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Prenatal whole exome sequencing detects a new homozygous fukutin (FKTN) mutation in a fetus with an ultrasound suspicion of familial Dandy-Walker malformation / Traversa, A; Bernardo, S; Paiardini, A; Giovannetti, A; Marchionni, E; Genovesi, Ml; Guadagnolo, D; Torres, B; Paolacci, S; Bernardini, L; Mazza, T; Carella, M; Caputo, V; Pizzuti, A. - In: MOLECULAR GENETICS & GENOMIC MEDICINE. - ISSN 2324-9269. - (2019). [10.1002/mgg3.1054]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1349570
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