RT Journal Article SR Electronic T1 Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 251 OP 255 DO 10.1136/jmg.2010.085563 VO 48 IS 4 A1 Pia Ostergaard A1 Michael A Simpson A1 Glen Brice A1 Sahar Mansour A1 Fiona C Connell A1 Alexandros Onoufriadis A1 Anne H Child A1 Jae Hwang A1 Kamini Kalidas A1 Peter S Mortimer A1 Richard Trembath A1 Steve Jeffery YR 2011 UL http://jmg.bmj.com/content/48/4/251.abstract AB 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.