title: Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency.
abstract: Aortic dilatation/dissection (AD) can occur spontaneously or in association with genetic syndromes, such as Marfan syndrome (MFS; caused by FBN1 mutations), MFS type 2 and Loeys-Dietz syndrome (associated with TGFBR1/TGFBR2 mutations), and Ehlers-Danlos syndrome (EDS) vascular type (caused by COL3A1 mutations). Although mutations in FBN1 and TGFBR1/TGFBR2 account for the majority of AD cases referred to us for molecular genetic testing, we have obtained negative results for these genes in a large cohort of AD patients, suggesting the involvement of additional genes or acquired factors. In this study we assessed the effect of COL3A1 deletions/duplications in this cohort. Multiplex ligation-dependent probe amplification (MLPA) analysis of 100 unrelated patients identified one hemizygous deletion of the entire COL3A1 gene. Subsequent microarray analyses and sequencing of breakpoints revealed the deletion size of 3,408,306 bp at 2q32.1q32.3. This deletion affects not only COL3A1 but also 21 other known genes (GULP1, DIRC1, COL5A2, WDR75, SLC40A1, ASNSD1, ANKAR, OSGEPL1, ORMDL1, LOC100129592, PMS1, MSTN, C2orf88, HIBCH, INPP1, MFSD6, TMEM194B, NAB1, GLS, STAT1, and STAT4), mutations in three of which (COL5A2, SLC40A1, and MSTN) have also been associated with an autosomal dominant disorder (EDS classical type, hemochromatosis type 4, and muscle hypertrophy). Physical and laboratory examinations revealed that true haploinsufficiency of COL3A1, COL5A2, and MSTN, but not that of SLC40A1, leads to a clinical phenotype. Our data not only emphasize the impact/role of COL3A1 in AD patients but also extend the molecular etiology of several disorders by providing hitherto unreported evidence for true haploinsufficiency of the underlying gene.
authors.affiliation: Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
authors.forename: Janine
authors.initials: J
authors.lastname: Meienberg
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.forename: Stefan
authors.initials: S
authors.lastname: Neuenschwander
authors.forename: Katharina
authors.initials: K
authors.lastname: Spanaus
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
authors.forename: Sira
authors.initials: S
authors.lastname: Alonso
authors.forename: Eliane
authors.initials: E
authors.lastname: Arnold
authors.forename: Caroline
authors.initials: C
authors.lastname: Henggeler
authors.forename: Stephan
authors.initials: S
authors.lastname: Regenass
authors.forename: Andrea
authors.initials: A
authors.lastname: Patrignani
authors.forename: Silvia
authors.initials: S
authors.lastname: Azzarello-Burri
authors.forename: Bernhard
authors.initials: B
authors.lastname: Steiner
authors.forename: Anders O H
authors.initials: AO
authors.lastname: Nygren
authors.forename: Thierry
authors.initials: T
authors.lastname: Carrel
authors.forename: Beat
authors.initials: B
authors.lastname: Steinmann
authors.forename: Gábor
authors.initials: G
authors.lastname: Mátyás
mesh_terms: D001018:Aortic Diseases / Q000235:genetics* / Q000473:pathology; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D019457:Chromosome Breakage; D024061:Collagen Type III / Q000235:genetics* / Q000648:ultrastructure; D024062:Collagen Type V / Q000235:genetics* / Q000648:ultrastructure; D015342:DNA Probes / Q000378:metabolism; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics*; D057898:Hemizygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D055435:Myostatin / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: C439971:COL3A1 protein, human; D024061:Collagen Type III; D024062:Collagen Type V; D015342:DNA Probes; D055435:Myostatin