title: First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm.
abstract: Genetic causes for abdominal aortic aneurysm (AAA) have not been identified and the role of genes associated with familial thoracic aneurysms in AAA has not been explored. We analyzed nine genes associated with familial thoracic aortic aneurysms, the vascular Ehlers-Danlos gene COL3A1 and the MTHFR p.Ala222Val variant in 155 AAA patients. The thoracic aneurysm genes selected for this study were the transforming growth factor-beta pathway genes EFEMP2, FBN1, SMAD3, TGBF2, TGFBR1, TGFBR2, and the smooth muscle cells genes ACTA2, MYH11 and MYLK. Sanger sequencing of all coding exons and exon-intron boundaries of these genes was performed. Patients with at least one first-degree relative with an aortic aneurysm were classified as familial AAA (n = 99), the others as sporadic AAA. We found 47 different rare heterozygous variants in eight genes: two pathogenic, one likely pathogenic, twenty-one variants of unknown significance (VUS) and twenty-three unlikely pathogenic variants. In familial AAA we found one pathogenic and segregating variant (COL3A1 p.Arg491X), one likely pathogenic and segregating (MYH11 p.Arg254Cys), and fifteen VUS. In sporadic patients we found one pathogenic (TGFBR2 p.Ile525Phefs*18) and seven VUS. Thirteen patients had two or more variants. These results show a previously unknown association and overlapping genetic defects between AAA and familial thoracic aneurysms, indicating that genetic testing may help to identify the cause of familial and sporadic AAA. In this view, genetic testing of these genes specifically or in a genome-wide approach may help to identify the cause of familial and sporadic AAA.
authors.affiliation: Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Koen M
authors.initials: KM
authors.lastname: van de Luijtgaarden
authors.forename: Daphne
authors.initials: D
authors.lastname: Heijsman
authors.forename: Alessandra
authors.initials: A
authors.lastname: Maugeri
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.forename: Hence J M
authors.initials: HJ
authors.lastname: Verhagen
authors.forename: Arne
authors.initials: A
authors.lastname: IJpma
authors.forename: Hennie T
authors.initials: HT
authors.lastname: Brüggenwirth
authors.forename: Danielle
authors.initials: D
authors.lastname: Majoor-Krakauer
mesh_terms: D000328:Adult; D000368:Aged; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D024061:Collagen Type III / Q000235:genetics*; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D018995:Myosin Heavy Chains / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*
chemical_list: C439971:COL3A1 protein, human; D024061:Collagen Type III; C509903:MYH11 protein, human; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018995:Myosin Heavy Chains