Abstract
Generalised lymphatic dysplasia (GLD) is characterised by extensive peripheral lymphoedema with visceral involvement. In some cases, it presents in utero with hydrops fetalis. Autosomal dominant and recessive inheritance has been reported. A large, non-consanguineous family with three affected siblings with generalised lymphatic dysplasia is presented. One child died aged 5 months, one spontaneously miscarried at 17 weeks gestation, and the third has survived with extensive lymphoedema. All three presented with hydrops fetalis. There are seven other siblings who are clinically unaffected. Linkage analysis produced two loci on chromosome 18, covering 22 Mb and containing 150 genes, one of which is CCBE1. A homozygous cysteine to serine change in CCBE1 has been identified in the proband, in a residue that is conserved across species. High density SNP analysis revealed homozygosity (a region of 900 kb) around the locus for CCBE1 in all three affected cases. This indicates a likely ancestral mutation that is common to both parents; an example of a homozygous mutation representing Identity by Descent (IBD) in this pedigree. Recent studies in zebrafish have shown this gene to be required for lymphangiogenesis and venous sprouting and are therefore supportive of our findings. In view of the conserved nature of the cysteine, the nature of the amino acid change, the occurrence of a homozygous region around the locus, the segregation within the family, and the evidence from zebrafish, we propose that this mutation is causative for the generalised lymphatic dysplasia in this family, and may be of relevance in cases of non-immune hydrops fetalis.
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Acknowledgments
KK, and FC were supported by the British Heart Foundation. PO is supported by the British Skin Foundation. We would like to thank the Reece Spence fund for their support. Much of this work was carried out in the Biomics Unit at SGUL. Members of the Lymphoedema Consortium not given in the author list are: Prof Alberto Smith, Professor Kevin Burnand (St Thomas’) Dr Anne Child (SGUL), Dr Mansoor Sarfarazi (Connecticut). We would like to thank Dr John Crolla and Dr Shuwen Huang (Wessex Regional Genetic Laboratory) for help in analysing the region with the mutation.
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F. Connell, K. Kalidas, P. Ostergaard made equal contributions to this work, and are listed in alphabetical order.
Authors in the consortium are listed in the Acknowledgements.
An erratum to this article can be found at http://dx.doi.org/10.1007/s00439-009-0772-0
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Connell, F., Kalidas, K., Ostergaard, P. et al. Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia. Hum Genet 127, 231–241 (2010). https://doi.org/10.1007/s00439-009-0766-y
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DOI: https://doi.org/10.1007/s00439-009-0766-y