title: Whole exome sequencing for the identification of a new mutation in TGFB2 involved in a familial case of non-syndromic aortic disease.
abstract: BACKGROUND
  Non-syndromic aortic disease (NSAD) is a frequently asymptomatic but potentially lethal disease characterised by familial cases of thoracic aortic aneurysms and dissections. This monogenic but genetically heterogeneous condition is primarily inherited as an autosomal dominant disorder with low penetrance and variable expression. Mutations in ACTA2, TGFBR1, TGFBR2, MYH11, SMAD3, MYLK, and FBN1 genes have been described but still, there are many unresolved familial cases.
  
  
  METHODS
  The whole exome of two distantly related and affected members of a Spanish family with multiple cases of NSAD was analysed through 5500 SOLiD(™) System for the identification of shared and putative pathogenic variants.
  
  
  RESULTS
  A new mutation termed c.C1042T:p.R348C (NM_001135599.2) was identified in TGFB2, a gene located in an evolutionary highly conserved region (Chr1: 218,519,577-218,617,961) that has been recently connected to this disease. The analysis of other family members using capillary sequencing confirmed cosegregation of the mutation with the disease and its incomplete penetrance.
  
  
  CONCLUSIONS
  The repeated implication of TGFB2 in the development of thoracic aortic aneurysms and dissections suggests that this gene should be considered during genetic diagnosis of this disease. An accurate diagnosis of affected individuals and additional family members at risk allows for a personalised and more efficient gene-based follow-up and treatment. Finally, the reiterative presence of common musculoskeletal and craniofacial additional features in patients with TGFB2 mutations suggests the existence of a new yet undefined connective tissue syndrome responsible for not only aortic dilation, but also for the other extracardiac alterations present in the affected patients.
authors.affiliation: Xenética de enfermidades cardiovasculares e oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain; Grupo de Medicina Xenómica IDIS-USC, Fundación Pública Galega de Medicina Xenómica, 15706 Santiago de Compostela, A Coruña, Spain. Electronic address: marina.gago@usc.es.
authors.forename: Marina
authors.initials: M
authors.lastname: Gago-Díaz
authors.affiliation: Xenética de enfermidades cardiovasculares e oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain; Grupo de Medicina Xenómica IDIS-USC, Fundación Pública Galega de Medicina Xenómica, 15706 Santiago de Compostela, A Coruña, Spain. Electronic address: alejandroj.blanco@usc.es.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Blanco-Verea
authors.affiliation: Servicio de Cardiología, Hospital Universitari Vall d'Hebron, Barcelona 08035, Spain. Electronic address: gisela.tt@gmail.com.
authors.forename: Gisela
authors.initials: G
authors.lastname: Teixidó-Turà
authors.affiliation: Servicio de Genética, Hospital Universitari Vall d'Hebron, Barcelona 08035, Spain. Electronic address: irenevalenzuelapalafoll@gmail.com.
authors.forename: Irene
authors.initials: I
authors.lastname: Valenzuela
authors.affiliation: Servicio de Genética, Hospital Universitari Vall d'Hebron, Barcelona 08035, Spain. Electronic address: migueldelcampocasanelles@gmail.com.
authors.forename: Miguel
authors.initials: M
authors.lastname: Del Campo
authors.affiliation: Servicio de Genética, Hospital Universitari Vall d'Hebron, Barcelona 08035, Spain. Electronic address: marborregan@gmail.com.
authors.forename: Mar
authors.initials: M
authors.lastname: Borregan
authors.affiliation: Grupo de Medicina Xenómica IDIS-USC, Fundación Pública Galega de Medicina Xenómica, 15706 Santiago de Compostela, A Coruña, Spain. Electronic address: beatriz.sobrino@usc.es.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sobrino
authors.affiliation: Grupo de Medicina Xenómica IDIS-USC, Fundación Pública Galega de Medicina Xenómica, 15706 Santiago de Compostela, A Coruña, Spain. Electronic address: jorge.amigo@usc.es.
authors.forename: Jorge
authors.initials: J
authors.lastname: Amigo
authors.affiliation: Servicio de Cardiología, Hospital Universitari Vall d'Hebron, Barcelona 08035, Spain. Electronic address: dgdorado@vhebron.net.
authors.forename: David
authors.initials: D
authors.lastname: García-Dorado
authors.affiliation: Servicio de Cardiología, Hospital Universitari Vall d'Hebron, Barcelona 08035, Spain. Electronic address: arturevangelistamasip@gmail.com.
authors.forename: Artur
authors.initials: A
authors.lastname: Evangelista
authors.affiliation: Grupo de Medicina Xenómica IDIS-USC, Fundación Pública Galega de Medicina Xenómica, 15706 Santiago de Compostela, A Coruña, Spain; Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah. Electronic address: angel.carracedo@usc.es.
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: Xenética de enfermidades cardiovasculares e oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain; Grupo de Medicina Xenómica IDIS-USC, Fundación Pública Galega de Medicina Xenómica, 15706 Santiago de Compostela, A Coruña, Spain. Electronic address: maria.brion@usc.es.
authors.forename: María
authors.initials: M
authors.lastname: Brion
mesh_terms: D000328:Adult; D000784:Aortic Dissection / Q000175:diagnosis / Q000235:genetics*; D017545:Aortic Aneurysm, Thoracic / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D053781:Transforming Growth Factor beta2 / Q000235:genetics*; D055815:Young Adult
chemical_list: C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2
keywords: Next generation sequencing; Non-syndromic aortic disease; TGFB2; Targeted exome capture; Whole exome sequencing