PT  - JOURNAL ARTICLE
AU  - Pia Ostergaard
AU  - Michael A Simpson
AU  - Glen Brice
AU  - Sahar Mansour
AU  - Fiona C Connell
AU  - Alexandros Onoufriadis
AU  - Anne H Child
AU  - Jae Hwang
AU  - Kamini Kalidas
AU  - Peter S Mortimer
AU  - Richard Trembath
AU  - Steve Jeffery
TI  - Rapid identification of mutations in <em>GJC2</em> in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype
AID  - 10.1136/jmg.2010.085563
DP  - 2011 Apr 01
TA  - Journal of Medical Genetics
PG  - 251--255
VI  - 48
IP  - 4
4099  - http://jmg.bmj.com/content/48/4/251.short
4100  - http://jmg.bmj.com/content/48/4/251.full
SO  - J Med Genet2011 Apr 01; 48
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.