title: Systematic identification of phenotypically enriched loci using a patient network of genomic disorders.
abstract: BACKGROUND
  Network medicine is a promising new discipline that combines systems biology approaches and network science to understand the complexity of pathological phenotypes. Given the growing availability of personalized genomic and phenotypic profiles, network models offer a robust integrative framework for the analysis of "omics" data, allowing the characterization of the molecular aetiology of pathological processes underpinning genetic diseases.
  
  
  METHODS
  Here we make use of patient genomic data to exploit different network-based analyses to study genetic and phenotypic relationships between individuals. For this method, we analyzed a dataset of structural variants and phenotypes for 6,564 patients from the DECIPHER database, which encompasses one of the most comprehensive collections of pathogenic Copy Number Variations (CNVs) and their associated ontology-controlled phenotypes. We developed a computational strategy that identifies clusters of patients in a synthetic patient network according to their genetic overlap and phenotype enrichments.
  
  
  RESULTS
  Many of these clusters of patients represent new genotype-phenotype associations, suggesting the identification of newly discovered phenotypically enriched loci (indicative of potential novel syndromes) that are currently absent from reference genomic disorder databases such as ClinVar, OMIM or DECIPHER itself.
  
  
  CONCLUSIONS
  We provide a high-resolution map of pathogenic phenotypes associated with their respective significant genomic regions and a new powerful tool for diagnosis of currently uncharacterized mutations leading to deleterious phenotypes and syndromes.
authors.affiliation: Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, and IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain. armando.reyes@embl.de.|CIBER de Enfermedades Raras (CIBERER), E-29071, Málaga, Spain. armando.reyes@embl.de.|Present address: The European Molecular Biology Laboratory Heidelberg, 69117, Heidelberg, Germany. armando.reyes@embl.de.
authors.forename: Armando
authors.identifier: http://orcid.org/0000-0002-0289-6889
authors.initials: A
authors.lastname: Reyes-Palomares
authors.affiliation: Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, and IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain.
authors.forename: Aníbal
authors.initials: A
authors.lastname: Bueno
authors.affiliation: Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, and IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain.|CIBER de Enfermedades Raras (CIBERER), E-29071, Málaga, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Rodríguez-López
authors.affiliation: Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, and IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain.|CIBER de Enfermedades Raras (CIBERER), E-29071, Málaga, Spain.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Medina
authors.affiliation: Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, and IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain.|CIBER de Enfermedades Raras (CIBERER), E-29071, Málaga, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Sánchez-Jiménez
authors.affiliation: The Genome Analysis Centre, Norwich Research Park, Norwich, NR4 7UH, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Corpas
authors.affiliation: Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, and IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain. ranea@uma.es.|CIBER de Enfermedades Raras (CIBERER), E-29071, Málaga, Spain. ranea@uma.es.
authors.forename: Juan A G
authors.initials: JA
authors.lastname: Ranea
mesh_terms: D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D056726:Genetic Association Studies; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D056426:Genetic Loci; D023281:Genomics / Q000379:methods*; D006801:Humans; D009154:Mutation; D010641:Phenotype