title: Efficient application of next-generation sequencing for the diagnosis of rare genetic syndromes.
abstract: OBJECTIVE
  The causes of intellectual disability, which affects 1%-3% of the general population, are highly heterogeneous and the genetic defect remains unknown in around 40% of patients. The application of next-generation sequencing is changing the nature of biomedical diagnosis. This technology has quickly become the method of choice for searching for pathogenic mutations in rare uncharacterised genetic diseases.
  
  
  METHODS
  Whole-exome sequencing was applied to a series of families affected with intellectual disability in order to identify variants underlying disease phenotypes.
  
  
  RESULTS
  We present data of three families in which we identified the disease-causing mutations and which benefited from receiving a clinical diagnosis: Cornelia de Lange, Cohen syndrome and Dent-2 disease. The genetic heterogeneity and the variability in clinical presentation of these disorders could explain why these patients are difficult to diagnose.
  
  
  CONCLUSIONS
  The accessibility to next-generation sequencing allows clinicians to save much time and cost in identifying the aetiology of rare diseases. The presented cases are excellent examples that demonstrate the efficacy of next-generation sequencing in rare disease diagnosis.
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona, Spain Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Madrigal
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona, Spain Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Alvarez-Mora
authors.affiliation: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Karlberg
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona, Spain Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Rodríguez-Revenga
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona, Spain Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain.
authors.forename: Dei M
authors.initials: DM
authors.lastname: Elurbe
authors.affiliation: Centre for Genomic Regulation (CRG) and UPF and CIBERESP, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Rabionet
authors.affiliation: Paediatrics Service, Hospital Universitario del Mar, Barcelona, Spain Paediatrics and Obstetrics Department, Universidad de Barcelona, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mur
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology, Medical School, University of Zaragoza, Zaragoza, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Pie
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Ballesta
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona, Spain Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Milà
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D010375:Pedigree; D013577:Syndrome; D059467:Transcriptome
keywords: DIAGNOSTICS; GENETICS; MOLECULAR GENETICS