title: Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation in COL5A1.
abstract: Different forms of Ehlers-Danlos syndrome (EDS) exist, with specific phenotypes and associated genes. Vascular EDS, caused by heterozygous mutations in the COL3A1 gene, is characterized by fragile vasculature with a high risk of catastrophic vascular events at a young age. Classic EDS, caused by heterozygous mutations in the COL5A1 or COL5A2 genes, is characterized by fragile, hyperextensible skin and joint laxity. To date, vessel rupture in four unrelated classic EDS patients with a confirmed COL5A1 mutation has been reported. We describe familial occurrence of a phenotype resembling vascular EDS in a mother and her two sons, who all died at an early age from arterial ruptures. Diagnostic Sanger sequencing in the proband failed to detect aberrations in COL3A1, COL1A1, COL1A2, TGFBR1, TGFBR2, SMAD3, and ACTA2. Next, the proband's DNA was analyzed using a next-generation sequencing approach targeting 554 genes linked to vascular disease (VASCULOME project). A novel heterozygous mutation in COL5A1 was detected, resulting in an essential glycine substitution at the C-terminal end of the triple helix domain (NM_000093.4:c.4610G>T; p.Gly1537Val). This mutation was also present in DNA isolated from autopsy material of the index's brother. No material was available from the mother, but the mutation was excluded in her parents, siblings and in the father of her sons, suggesting that the COL5A1 mutation occurred in the mother's genome de novo. In conclusion, we report familial occurrence of lethal arterial events caused by a COL5A1 mutation.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Glen R
authors.initials: GR
authors.lastname: Monroe
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Harakalova
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Saskia N
authors.initials: SN
authors.lastname: van der Crabben
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: Majoor-Krakauer
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Aida M
authors.initials: AM
authors.lastname: Bertoli-Avella
authors.affiliation: Department of Vascular Surgery, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Frans L
authors.initials: FL
authors.lastname: Moll
authors.affiliation: Department of Vascular Surgery, Bethesda Hospital, Hoogeveen, The Netherlands.
authors.forename: Björn I
authors.initials: BI
authors.lastname: Oranen
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Dooijes
authors.affiliation: Department of Pathology, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Aryan
authors.initials: A
authors.lastname: Vink
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Nine V
authors.initials: NV
authors.lastname: Knoers
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Maugeri
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Gijs
authors.initials: G
authors.lastname: van Haaften
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Annette F
authors.initials: AF
authors.lastname: Baas
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001019:Aortic Rupture / Q000097:blood / Q000235:genetics* / Q000473:pathology; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D024062:Collagen Type V / Q000235:genetics* / Q000378:metabolism; D004535:Ehlers-Danlos Syndrome / Q000097:blood / Q000235:genetics* / Q000473:pathology; D017809:Fatal Outcome; D005260:Female; D015870:Gene Expression; D006470:Hemorrhage / Q000097:blood / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: C439971:COL3A1 protein, human; C530725:COL5A1 protein, human; D024061:Collagen Type III; D024062:Collagen Type V
keywords: COL3A1; COL5A1; Ehlers­­-Danlos Syndrome (EDS)