CCBE1 Mutation in Two Siblings, One Manifesting Lymphedema-Cholestasis Syndrome, and the Other, Fetal Hydrops

Sohela Shah, Laura K. Conlin, Luis Gomez Carbajal, Øystein Aagenaes, Kristin Eiklid, A. S. Knisely, Michael T. Mennuti, Randolph P. Matthews, Nancy B. Spinner, Laura N. Bull

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere75770
JournalPloS one
Volume8
Issue number9
DOIs
StatePublished - Sep 26 2013

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Hydrops Fetalis
cholestasis
Siblings
homozygosity
Genes
mutation
Mutation
Cholestasis
Chromosomes
chromosomes
Intrahepatic Cholestasis
Chromosomes, Human, Pair 18
Chromosomes, Human, Pair 15
Lymphedema
genes
Polymorphism
limbs (animal)
genotyping
single nucleotide polymorphism
Single Nucleotide Polymorphism

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Shah, S., Conlin, L. K., Gomez Carbajal, L., Aagenaes, Ø., Eiklid, K., Knisely, A. S., ... Bull, L. N. (2013). CCBE1 Mutation in Two Siblings, One Manifesting Lymphedema-Cholestasis Syndrome, and the Other, Fetal Hydrops. PloS one, 8(9), [e75770]. https://doi.org/10.1371/journal.pone.0075770

CCBE1 Mutation in Two Siblings, One Manifesting Lymphedema-Cholestasis Syndrome, and the Other, Fetal Hydrops. / Shah, Sohela; Conlin, Laura K.; Gomez Carbajal, Luis; Aagenaes, Øystein; Eiklid, Kristin; Knisely, A. S.; Mennuti, Michael T.; Matthews, Randolph P.; Spinner, Nancy B.; Bull, Laura N.

In: PloS one, Vol. 8, No. 9, e75770, 26.09.2013.

Research output: Contribution to journalArticle

Shah, S, Conlin, LK, Gomez Carbajal, L, Aagenaes, Ø, Eiklid, K, Knisely, AS, Mennuti, MT, Matthews, RP, Spinner, NB & Bull, LN 2013, 'CCBE1 Mutation in Two Siblings, One Manifesting Lymphedema-Cholestasis Syndrome, and the Other, Fetal Hydrops', PloS one, vol. 8, no. 9, e75770. https://doi.org/10.1371/journal.pone.0075770
Shah S, Conlin LK, Gomez Carbajal L, Aagenaes Ø, Eiklid K, Knisely AS et al. CCBE1 Mutation in Two Siblings, One Manifesting Lymphedema-Cholestasis Syndrome, and the Other, Fetal Hydrops. PloS one. 2013 Sep 26;8(9). e75770. https://doi.org/10.1371/journal.pone.0075770
Shah, Sohela ; Conlin, Laura K. ; Gomez Carbajal, Luis ; Aagenaes, Øystein ; Eiklid, Kristin ; Knisely, A. S. ; Mennuti, Michael T. ; Matthews, Randolph P. ; Spinner, Nancy B. ; Bull, Laura N. / CCBE1 Mutation in Two Siblings, One Manifesting Lymphedema-Cholestasis Syndrome, and the Other, Fetal Hydrops. In: PloS one. 2013 ; Vol. 8, No. 9.
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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.",
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AU - Aagenaes, Øystein

AU - Eiklid, Kristin

AU - Knisely, A. S.

AU - Mennuti, Michael T.

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