title: A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm.
abstract: A number of autosomal dominantly inherited disorders, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), are associated with predisposition to thoracic aortic aneurysms and dissections (TAADs). In the majority of cases, mutations in genes encoding components of the transforming growth factor-β (TGF-β) signaling pathway, such as FBN1, TGFBR1, TGFBR2 and SMAD3, underlie the disease. Recently, a familial syndromic form of TAAD with other clinical features that overlap the MFS-LDS spectrum has been described to be caused by heterozygous loss-of-function mutations in TGFB2, encoding the TGF-β2 ligand of TGF-β serine/threonine kinase receptors (TGFBRs). We analyzed the TGFB2 gene by sequencing in a cohort of 88 individuals with a Marfan-like phenotype and/or TAAD, who did not have mutations in known genes causing thoracic aortic disease. We identified the novel heterozygous c.1165dupA mutation in exon 7 of TGFB2 in three members of a family, a 51-year-old male, his brother and nephew with aortic aneurysms, cervical arterial tortuosity and/or skeletal abnormalities as well as craniofacial dysmorphisms. The 1-bp duplication causes a frameshift leading to a stable transcript with a premature stop codon after seven TGF-β2-unrelated amino acids (p.Ser389Lysfs*8). As the resulting protein is unlikely functional and by considering data from the literature, we support the notion that functional haploinsufficiency for TGF-β2 predisposes to thoracic aortic disease. Taken together, TGFB2 is a rarely mutated gene in patients with syndromic TAAD, and the clinical features of our TGFB2 mutation-positive individuals fit in the scheme of LDS, rather than MFS-related disorders.
authors.affiliation: Department of Human Genetics, Center for Obstetrics and Paediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Leutermann
authors.affiliation: Department of Cardiology and Cardiovascular Surgery, University Heart Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Sheikhzadeh
authors.affiliation: Department of Cardiology and Cardiovascular Surgery, University Heart Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Brockstädt
authors.affiliation: Department of Cardiology and Cardiovascular Surgery, University Heart Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Rybczynski
authors.affiliation: Department of Human Genetics, Center for Obstetrics and Paediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: van Rahden
authors.affiliation: Department of Human Genetics, Center for Obstetrics and Paediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
authors.affiliation: Department of Cardiology and Cardiovascular Surgery, University Heart Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Yskert
authors.initials: Y
authors.lastname: von Kodolitsch
authors.affiliation: Department of Human Genetics, Center for Obstetrics and Paediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Rosenberger
mesh_terms: D000293:Adolescent; D000328:Adult; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000473:pathology; D005190:Family; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D010375:Pedigree; D053781:Transforming Growth Factor beta2 / Q000235:genetics*
chemical_list: C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2