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Efficient application of next-generation sequencing for the diagnosis of rare genetic syndromes
  1. Irene Madrigal1,2,
  2. Maria Isabel Alvarez-Mora1,2,
  3. Olof Karlberg3,
  4. Laia Rodríguez-Revenga1,2,
  5. Dei M Elurbe1,2,
  6. Raquel Rabionet4,
  7. Antonio Mur5,6,
  8. Juan Pie7,
  9. Francisca Ballesta1,
  10. Sascha Sauer8,
  11. Ann-Christine Syvänen3,
  12. Montserrat Milà1,2
  1. 1Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona, Spain
  2. 2Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain
  3. 3Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  4. 4Centre for Genomic Regulation (CRG) and UPF and CIBERESP, Barcelona, Spain
  5. 5Paediatrics Service, Hospital Universitario del Mar, Barcelona, Spain
  6. 6Paediatrics and Obstetrics Department, Universidad de Barcelona, Barcelona, Spain
  7. 7Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology, Medical School, University of Zaragoza, Zaragoza, Spain
  8. 8Max-Planck Institute for Molecular Genetics, Berlin, Germany
  1. Correspondence to Dr Montserrat Milà Recasens, Biochemistry and Molecular Genetics Service, Hospital Clínic, C/Villarroel, 170 08036 Barcelona, Spain; mmila{at}


Aims 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.


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