title: Exome sequencing identifies a novel heterozygous TGFB3 mutation in a disorder overlapping with Marfan and Loeys-Dietz syndrome.
abstract: Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are clinically related autosomal dominant systemic connective tissue disorders. Although mutations in several genes of the TGF-beta signalling and related pathways have been identified in the past (e.g. FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2), there are still many individuals with "marfanoid" phenotypes in whom no causative mutations are identified. We performed whole exome sequencing in two of three affected individuals from a family with phenotypic features overlapping MFS and LDS. The two affected children and their affected father had tall stature, arachnodactyly, hyperextensible joints, hypertelorism, bifid uvula, but no cardiac involvement, aortic dilation or eye involvement. We detected a novel heterozygous mutation in TGFB3, c.898C>G, predicting the missense substitution p.Arg300Gly. Sanger sequencing confirmed the mutation and its segregation with the phenotype. The first two TGFB3 mutations were reported previously in two unrelated individuals with marfanoid features: one individual with growth retardation carried a heterozygous loss-of-function mutation (c.1226G>A; p.Cys409Tyr; Rienhoff et al., 2013), whereas a child with overgrowth carried a mutation in the same codon as the mutation identified in the three affected individuals reported here (c.899G>A; p.Arg300Gln; Matyas et al., 2014). The mutations at codon Arg300 presumably lead to increased TGF-beta signalling, suggesting that the short or tall stature seen in patients with TGFB3 mutations may result from opposing effects of mutations on TGF-beta signalling. Thus, we add a novel human TGFB3 mutation, contribute to the clinical delineation of the emerging connective tissue disorder tentatively called Rienhoff syndrome and compare the data with a very recent report (Bertoli-Avella et al., 2015) on TGFB3 mutations associated with aortic aneurysms or dissections.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany. Electronic address: alma.kuechler@uni-due.de.
authors.forename: Alma
authors.initials: A
authors.lastname: Kuechler
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Pediatric Cardiology, University Children's Hospital Muenster, Muenster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kotthoff
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
mesh_terms: D000293:Adolescent; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D055947:Loeys-Dietz Syndrome / Q000235:genetics*; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D053782:Transforming Growth Factor beta3 / Q000235:genetics*
chemical_list: C509044:TGFB3 protein, human; D053782:Transforming Growth Factor beta3
keywords: Bifid uvula; Exome sequencing; Loeys-Dietz syndrome; Marfan syndrome; TGFB3; Tall stature