CCBE1 mutation in two siblings, one manifesting lymphedema-cholestasis syndrome, and the other, fetal hydrops

• Published in: PloS one Vol. 8; no. 9; p. e75770
• Main Authors: Shah, Sohela, Conlin, Laura K, Gomez, Luis, Aagenaes, Øystein, Eiklid, Kristin, Knisely, A S, Mennuti, Michael T, Matthews, Randolph P, Spinner, Nancy B, Bull, Laura N
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26-09-2013; Public Library of Science (PLoS)
• Subjects: Bile; Calcium-Binding Proteins - genetics; Cholestasis; Cholestasis - genetics; Chromosome 15; Chromosome 18; Craniofacial Abnormalities - genetics; Dysplasia; Edema; Female; Fetuses; Genes; Genital Diseases, Male - genetics; Genomes; Genotype; Genotyping; Hereditary diseases; Homozygosity; Homozygote; Humans; Hydrops Fetalis - genetics; Infant; Liver; Lymphangiectasis, Intestinal - genetics; Lymphedema; Lymphedema - genetics; Male; Mutation; Mutation - genetics; Neonates; Parents; Phenotype; Polymorphism; Polymorphism, Single Nucleotide - genetics; Pregnancy; Rodents; Siblings; Single-nucleotide polymorphism; Tumor Suppressor Proteins - genetics; San Francisco California; California; United States > US; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0075770

Lymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb. LCS was originally described in a Norwegian kindred in which a locus, LCS1, was mapped to a 6.6cM region on chromosome 15. Mutations in CCBE1 on chromosome 18 have been reported in some cases of lymphatic dysplasia, but not in LCS.
Consanguineous parents of Mexican ancestry had a child with LCS who did not exhibit extended homozygosity in the LCS1 region. A subsequent pregnancy was electively terminated due to fetal hydrops. We performed whole-genome single nucleotide polymorphism genotyping to identify regions of homozygosity in these siblings, and sequenced promising candidate genes.
Both siblings harbored a homozygous mutation in CCBE1, c.398 T>C, predicted to result in the missense change p.L133P. Regions containing known 'cholestasis genes' did not demonstrate homozygosity in the LCS patient.
Mutations in CCBE1 may yield a phenotype not only of lymphatic dysplasia, but also of LCS or fetal hydrops; however, the possibility that the sibling with LCS also carries a homozygous mutation in an unidentified gene influencing cholestasis cannot be excluded.