A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm
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A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm. / Leutermann, Ruth; Sheikhzadeh, Sara; Brockstädt, Lars; Rybczynski, Meike; van Rahden, Vanessa; Kutsche, Kerstin; Kodolitsch, Yskert; Rosenberger, Georg.
In: EUR J HUM GENET, Vol. 22, 06.11.2013, p. 944-948.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm
AU - Leutermann, Ruth
AU - Sheikhzadeh, Sara
AU - Brockstädt, Lars
AU - Rybczynski, Meike
AU - van Rahden, Vanessa
AU - Kutsche, Kerstin
AU - Kodolitsch, Yskert
AU - Rosenberger, Georg
PY - 2013/11/6
Y1 - 2013/11/6
N2 - 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.European Journal of Human Genetics advance online publication, 6 November 2013; doi:10.1038/ejhg.2013.252.
AB - 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.European Journal of Human Genetics advance online publication, 6 November 2013; doi:10.1038/ejhg.2013.252.
U2 - 10.1038/ejhg.2013.252
DO - 10.1038/ejhg.2013.252
M3 - SCORING: Journal article
C2 - 24193348
VL - 22
SP - 944
EP - 948
JO - EUR J HUM GENET
JF - EUR J HUM GENET
SN - 1018-4813
ER -