title: Ehlers-Danlos syndrome with lethal cardiac valvular dystrophy in males carrying a novel splice mutation in FLNA.
abstract: Filamin A is an X-linked, ubiquitous actin-binding protein whose mutations are associated to multiple disorders with limited genotype-phenotype correlations. While gain-of-function mutations cause various bone dysplasias, loss-of-function variants are the most common cause of periventricular nodular heterotopias with variable soft connective tissue involvement, as well as X-linked cardiac valvular dystrophy (XCVD). The term "Ehlers-Danlos syndrome (EDS) with periventricular heterotopias" has been used in females with neurological, cardiovascular, integument and joint manifestations, but this nosology is still a matter of debate. We report the clinical and molecular update of an Italian family with an X-linked recessive soft connective tissue disorder and which was described, in 1975, as the first example of EDS type V of the Berlin nosology. The cutaneous phenotype of the index patient was close to classical EDS and all males died for a lethal cardiac valvular dystrophy. Whole exome sequencing identified the novel c.1829-1G>C splice variation in FLNA in two affected cousins. The nucleotide change was predicted to abolish the canonical splice acceptor site of exon 13 and to activate a cryptic acceptor site 15 bp downstream, leading to in frame deletion of five amino acid residues (p.Phe611_Gly615del). The predicted in frame deletion clusters with all the mutations previously identified in XCVD and falls within the N-terminus rod 1 domain of filamin A. Our findings expand the male-specific phenotype of FLNA mutations that now includes classical-like EDS with lethal cardiac valvular dystrophy, and offer further insights for the genotype-phenotype correlations within this spectrum. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ritelli
authors.affiliation: Unit of Clinical Genetics, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Morlino
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Giacopuzzi
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Carini
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cinquina
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Chiarelli
authors.affiliation: Unit of Clinical Genetics, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Majore
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Colombi
authors.affiliation: Unit of Clinical Genetics, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Castori
mesh_terms: D002648:Child; D002675:Child, Preschool; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis* / Q000235:genetics*; D059472:Exome; D017809:Fatal Outcome; D005260:Female; D064448:Filamins / Q000235:genetics*; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites
chemical_list: C578663:FLNA protein, human; D064448:Filamins; D022821:RNA Splice Sites
keywords: Ehlers-Danlos syndrome; atrophic scarring; connective tissue; filamin A; genotype-phenotype correlations