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Letters to the Editor

CFC1 Gene Mutation and Biliary Atresia With Polysplenia Syndrome

Jacquemin, Emmanuel*†; Cresteil, Danièle; Raynaud, Nicole; Hadchouel, Michelle*†

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Journal of Pediatric Gastroenterology and Nutrition: March 2002 - Volume 34 - Issue 3 - p 326
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To the Editor:

Biliary atresia is the most frequent cause of neonatal cholestasis and the most frequent indication for liver transplantation in children. Its cause is unknown but usually not considered genetic in origin, although rare familial cases have been reported (1). About 10% of infants with biliary atresia also have additional congenital defects, many of them belonging to left–right axis abnormalities, such as situs inversus, asplenia/polysplenia, and cardiac anomalies. These facts may suggest involvement of genetic factors (1,2). Animal models have shown that alterations in left–right specification could affect biliary development (1). CFC1 gene (encoding the cryptic protein) plays a role in establishing the left–right axis. Heterozygous CFC1 gene mutations have been recently identified in nine patients with laterality sequence defects, among whom one was diagnosed with associated biliary atresia (3). We now report the existence of heterozygous CFC1 gene mutations in two brothers born from nonconsanguineous parents. Both boys carry laterality defects associated with biliary atresia in one (Fig. 1).

FIG. 1.
FIG. 1.:
Pedigree and mutation analysis of CFC1 gene in a family. Semifilled symbol indicates heterozygous status for N21H and R47Q mutations. DNA sequence analysis was performed in each individual reported here, after obtaining informed consent in accordance with protocols for human studies approved by our medical center.

Sequencing of the complete six exons and the corresponding intron–exon junctions of the CFC1 gene (3) has allowed identification of two amino acid changes, N21H (61A→C, 63T→C) and R47Q (140G→A), located on the common maternal allele. These two amino acid changes were not detected in the more than 200 chromosomes of control individuals. Therefore, the disease-causing effect of these mutations should be considered. Although unlikely, a rare polymorphism, previously suggested (3), cannot be completely excluded. These sequence changes were inherited from a phenotypically normal mother, evoking incomplete penetrance. In addition, the haplotype P196P (588C→A) and L202L (606G→C) reported in one patient with laterality defect also was present in the brothers reported here (3). This haplotype was inherited from a phenotypically normal father. Along with a previous report (3), this study suggests that heterozygous CFC1 mutation may be associated with biliary atresia and laterality defects, and warrants a further search for CFC1 mutation. Heterozygous CFC1 mutation alone probably is not responsible for the human phenotype, but it may represent a predisposition (3). Other genetic or environmental factors probably are involved in the disease phenotype, and this could explain the inconstant recurrence within families (1).

*†Emmanuel Jacquemin

†Danièle Cresteil

†Nicole Raynaud

*†Michelle Hadchouel

REFERENCES

1. Bates MD, Bucuvalas JC, Alonso MH, et al. Biliary atresia: pathogenesis and treatment. Semin Liver Dis 1998; 18:281–93.
2. Carmi R, Magee CA, Neill CA, et al. Extrahepatic biliary atresia and associated anomalies: etiologic heterogeneity suggested by distinctive patterns of associations. Am J Med Genet 1993; 45:683–93.
3. Bamford RN, Roessler E, Burdine RD, et al. Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet 2000; 26:365–9.
© 2002 Lippincott Williams & Wilkins, Inc.