title: Vascular Ehlers-Danlos Syndrome in siblings with biallelic COL3A1 sequence variants and marked clinical variability in the extended family.
abstract: Vascular Ehlers-Danlos Syndrome (vEDS), also known as EDS type IV, is considered to be an autosomal dominant disorder caused by sequence variants in COL3A1, which encodes the chains of type III procollagen. We identified a family in which there was marked clinical variation with the earliest death due to extensive aortic dissection at age 15 years and other family members in their eighties with no complications. The proband was born with right-sided clubfoot but was otherwise healthy until he died unexpectedly at 15 years. His sister, in addition to signs consistent with vascular EDS, had bilateral frontal and parietal polymicrogyria. The proband and his sister each had two COL3A1 sequence variants, c.1786C>T, p.(Arg596*) in exon 26 and c.3851G>A, p.(Gly1284Glu) in exon 50 on different alleles. Cells from the compound heterozygote produced a reduced amount of type III procollagen, all the chains of which had abnormal electrophoretic mobility. Biallelic sequence variants have a significantly worse outcome than heterozygous variants for either null mutations or missense mutations, and frontoparietal polymicrogyria may be an added phenotype feature. This genetic constellation provides a very rare explanation for marked intrafamilial clinical variation due to sequence variants in COL3A1.
authors.affiliation: Division of Child and Adolescent Health, Medical Genetics Department, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Agnete
authors.initials: A
authors.lastname: Jørgensen
authors.affiliation: Division of Child and Adolescent Health, Medical Genetics Department, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Toril
authors.initials: T
authors.lastname: Fagerheim
authors.affiliation: TRS, National Resource Centre for Rare Disorders, Sunnaas Rehabilitation Hospital, Nesoddtangen, Norway.
authors.forename: Svend
authors.initials: S
authors.lastname: Rand-Hendriksen
authors.affiliation: Division of Cardiothoracic and Respiratory Medicine, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Per I
authors.initials: PI
authors.lastname: Lunde
authors.affiliation: Division of Diagnostic Services, Department of Radiology, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Torgrim O
authors.initials: TO
authors.lastname: Vorren
authors.affiliation: Department of Pathology, Seattle, WA,USA.
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Pepin
authors.affiliation: Department of Pathology, Seattle, WA,USA.
authors.forename: Dru F
authors.initials: DF
authors.lastname: Leistritz
authors.affiliation: 1] Department of Pathology, Seattle, WA,USA [2] Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Byers
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000783:Aneurysm / Q000175:diagnosis / Q000235:genetics*; D002478:Cells, Cultured; D024061:Collagen Type III / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D035781:Siblings
chemical_list: C439971:COL3A1 protein, human; D024061:Collagen Type III