title: PRKG1 and genetic diagnosis of early-onset thoracic aortic disease.
abstract: BACKGROUND
  The 20% of thoracic aortic aneurysms and dissections independent from the main connective tissue syndromes and expected to be familial has gained importance over the past years. The more frequent pattern of inheritance of these nonsyndromic cases is autosomal dominant with incomplete penetrance and variable expression. Although many candidate genes exist, unresolved familial cases suggest still unravelled genetic variation. The main purpose of this study was to establish the genetic diagnosis of one of those.
  
  
  METHODS
  To begin with, we applied a candidate gene approach based on both traditional and a customized massive parallel sequencing panel, followed by Illumina HiSeq 2000 whole exome sequencing of four family members affected by early-onset thoracic aortic disease and two unaffected relatives. We prioritized whole exome sequencing results based on variant location, type and frequency in general population databases and performed segregation analysis in 14 family members using traditional sequencing.
  
  
  RESULTS
  After the negative results we obtained with candidate gene approaches, the analysis and prioritization of whole exome sequencing results brought out the heterozygote c.530G>A:p.Arg177Gln PRKG1 variant (NM_001098512), located in one of the aortic smooth muscle cell contractile apparatus genes. This candidate variant segregated with thoracic aortic disease, as it was present in seven affected and absent in five unaffected family members, further supporting its causality.
  
  
  CONCLUSIONS
  This was the second time PRKG1 was associated with thoracic aortic disease, highlighting and reaffirming it as a strong candidate for gene-based diagnosis of nonsyndromic early-onset cases.
authors.affiliation: Xenética de Enfermidades Cardiovasculares e Oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain.|Medicina Xenómica, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela, Universidade de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain.
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, Santiago de Compostela, A Coruña, Spain.|Medicina Xenómica, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela, Universidade de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Blanco-Verea
authors.affiliation: Servei de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Gisela
authors.initials: G
authors.lastname: Teixidó
authors.affiliation: Servei de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: Huguet
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation, Barcelona, Spain.|Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation, Barcelona, Spain.|Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Steven
authors.initials: S
authors.lastname: Laurie
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation, Barcelona, Spain.|Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.affiliation: Medicina Xenómica, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela, Universidade de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain.|Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Carracedo
authors.affiliation: Servei de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Artur
authors.initials: A
authors.lastname: Evangelista
authors.affiliation: Xenética de Enfermidades Cardiovasculares e Oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain.|Medicina Xenómica, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela, Universidade de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Brion
mesh_terms: D000328:Adult; D017668:Age of Onset; D000784:Aortic Dissection / Q000235:genetics*; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics*; D002648:Child; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D013030:Spain
chemical_list: D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569718:PRKG1 protein, human
keywords: Gene-based clinical diagnosis; PRKG1; nonsyndromic thoracic aortic disease; whole exome sequencing