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

P Ostergaard, MA Simpson, G Brice… - Journal of medical …, 2011 - jmg.bmj.com
P Ostergaard, MA Simpson, G Brice, S Mansour, FC Connell, A Onoufriadis, AH Child…
Journal of medical genetics, 2011jmg.bmj.com
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 …
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.
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