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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Sohela Shah, Laura K Conlin, Luis Gomez, Øystein Aagenaes, Kristin Eiklid, A S Knisely, Michael T Mennuti, Randolph P Matthews, Nancy B Spinner, Laura N Bull
• Journal: PloS one (PLoS One) Vol. 8 Issue 9 Pg. e75770 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24086631 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• Calcium-Binding Proteins (genetics)
• Cholestasis (genetics)
• Craniofacial Abnormalities (genetics)
• Female
• Genital Diseases, Male (genetics)
• Genotype
• Homozygote
• Humans
• Hydrops Fetalis (genetics)
• Infant
• Lymphangiectasis, Intestinal (genetics)
• Lymphedema (genetics)
• Male
• Mutation (genetics)
• Phenotype
• Polymorphism, Single Nucleotide (genetics)
• Siblings
• Tumor Suppressor Proteins (genetics)