Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia

Hum Genet. 2010 Feb;127(2):231-41. doi: 10.1007/s00439-009-0766-y. Epub 2009 Nov 13.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Calcium-Binding Proteins / genetics*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 18 / genetics
  • DNA Mutational Analysis / methods*
  • Family Health
  • Fatal Outcome
  • Female
  • Fetal Death
  • Genes, Recessive
  • Genetic Linkage*
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Infant
  • Lymphedema / genetics*
  • Lymphedema / pathology
  • Male
  • Mutation*
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Tumor Suppressor Proteins / genetics*


  • CCBE1 protein, human
  • Calcium-Binding Proteins
  • Tumor Suppressor Proteins