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Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype
  1. Pia Ostergaard1,
  2. Michael A Simpson2,
  3. Glen Brice3,
  4. Sahar Mansour3,
  5. Fiona C Connell4,
  6. Alexandros Onoufriadis2,
  7. Anne H Child5,
  8. Jae Hwang1,
  9. Kamini Kalidas1,
  10. Peter S Mortimer6,
  11. Richard Trembath2,
  12. Steve Jeffery1
  1. 1Medical Genetics, St George's, University of London, London, UK
  2. 2Department of Medical and Molecular Genetics, King's College London, School of Medicine, Guy's Hospital, London, UK
  3. 3Southwest Thames Regional Genetics Service, St. George's, University of London, London, UK
  4. 4Clinical Genetics Department, Guy's Hospital, NHS Foundation Trust, London, UK
  5. 5Department of Cardiac and Vascular Sciences, St George's, University of London, London, UK
  6. 6Department of Cardiac and Vascular Sciences (Dermatology), St George's, University of London, London, UK
  1. Correspondence to Professor Steve Jeffery, Medical Genetics, St George's, University of London, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK; sggt100{at}


Background Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George's Hospital.

Methods Linkage analysis was used to determine a locus, and exome sequencing was employed to look for causative variants.

Results Linkage analysis revealed cosegregation of a 16.1 Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. Whole exome sequencing in a single affected individual was undertaken, and the search for the causative variant was focused to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. NVL and GJC2 were sequenced in an additional cohort of individuals with a similar phenotype and non-synonymous variants were found in GJC2 in four additional families.

Conclusion This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery, and suggests that the phenotype produced by GJC2 mutations is predominantly one of 4 limb lymphoedema.

  • Other cardiovascular medicine
  • genetics
  • clinical genetics
  • molecular genetics

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  • PO and MAS contributed equally to this work.

  • Funding The authors acknowledge the financial support from the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust.

  • Competing interests None declared.

  • Ethics approval This study was conducted with the approval of the Wandsworth Local Research Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.