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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.

Ostergaard, P; Simpson, MA; Brice, G; Mansour, S; Connell, FC; Onoufriadis, A; Child, AH; Hwang, J; Kalidas, K; Mortimer, PS; et al. Ostergaard, P; Simpson, MA; Brice, G; Mansour, S; Connell, FC; Onoufriadis, A; Child, AH; Hwang, J; Kalidas, K; Mortimer, PS; Trembath, R; Jeffery, S (2011) Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. JOURNAL OF MEDICAL GENETICS, 48 (4). 251 - 255 (5). ISSN 0022-2593 https://doi.org/10.1136/jmg.2010.085563
SGUL Authors: Child, Anne Hawthorne Jeffery, Stephen Kalidas, Kamini Mortimer, Peter Sydney Ostergaard, Pia Mansour, Sahar Brice, Glen Worthington

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Abstract

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.

Item Type: Article
Additional Information: PubMed ID: 21266381
Keywords: Connexins, Female, Genetic Linkage, Humans, Lymphatic Diseases, Male, Mutation, Pedigree, Phenotype, Sequence Analysis, DNA, Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, MERZBACHER-LIKE-DISEASE, RECESSIVE ROBINOW-SYNDROME, BRACHYDACTYLY TYPE-B, HEREDITARY LYMPHEDEMA, TYROSINE KINASE, TRANSCRIPTION FACTOR, MISSENSE MUTATIONS, GENE, ROR2, DYSFUNCTION
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cardiac (INCCCA)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: JOURNAL OF MEDICAL GENETICS
ISSN: 0022-2593
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Dates:
DateEvent
1 April 2011Published
Web of Science ID: WOS:000288784300006
URI: http://openaccess.sgul.ac.uk/id/eprint/100981
Publisher's version: https://doi.org/10.1136/jmg.2010.085563

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