Identification of mutations in GJC2 in primary lymphedemaoe

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Identification of mutations in GJC2 in primary lymphedemaoe

Postby patoco » Sat Sep 17, 2011 10:22 am

Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.

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;


Medical Genetics, St George's, University of London, and Guy's Hospital, London SW17 ORE, UK.



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.

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

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.

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.

British Med Journal
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