SNOMEDCT: 699189004; ORPHA: 168583;
Cytogenetic location: 16q22 Genomic coordinates (GRCh38) : 16:66,600,001-74,100,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22 | North American Indian childhood cirrhosis | 604901 | 2 |
Weber et al. (1981) described an isolated nonsyndromic form of cholestasis in Ojibway-Cree children from First Nations communities in the Abitibi region of northwestern Quebec, Canada. The disease typically presents, in a child who is otherwise well, with transient neonatal jaundice that progresses to biliary cirrhosis requiring hepatic transplantation in childhood or early adulthood. The biochemical and histopathologic features of the disease suggest involvement of the bile ducts rather than of the bile canaliculi. These include elevated gamma-glutamyltransferase and alkaline phosphatase levels and, typically, marked fibrosis around portal bile ducts. Called North American Indian childhood cirrhosis, the carrier frequency in at-risk populations was estimated to be approximately 9%. Betard et al. (2000) noted that NAIC appears to be clinically distinct from previously described nonsyndromic family cholestases (see 211600) because of its marked cholangiopathic features and severe degree of fibrosis on liver histology.
Hypothesizing that a major founder mutation underlies most or all cases of NAIC, Betard et al. (2000) used a DNA-pooling strategy to search for an excess of shared homozygosity due to identity by descent among patients, compared with their unaffected first-degree relatives. They studied 13 patients, 16 unaffected sibs, and 22 parents from 5 families and identified a chromosome 16q segment shared by all affected individuals. Assuming a completely penetrant autosomal recessive mode of inheritance, a maximum lod score of 4.44 was observed for a recombination fraction of zero with marker D16S3067. A 5-marker haplotype spanning 4.9 cM was shared by all patients. Thus the candidate gene appeared to be located at 16q22.
Chagnon et al. (2002) demonstrated that NAIC has an autosomal recessive pattern of inheritance.
In affected members of 5 families segregating NAIC, Chagnon et al. (2002) identified a homozygous missense mutation in the CIRH1A (UTP4) gene (R565W; 607456.0001). However, Lek et al. (2016) found that the ExAC database contained 222 heterozygous and 4 homozygous Latino individuals carrying the CIRH1A R565W mutation, for a population frequency of 1.92%. The 4 homozygous individuals had no history of liver disease; recontact with 2 of them revealed normal liver function at ages 56 and 53. Using the ACMG guidelines (Richards et al., 2015), Lek et al. (2016) classified this variant as benign.
Betard, C., Rasquin-Weber, A., Brewer, C., Drouin, E., Clark, S., Verner, A., Darmond-Zwaig, C., Fortin, J., Mercier, J., Chagnon, P., Fujiwara, T. M., Morgan, K., Richter, A., Hudson, T. J., Mitchell, G. A. Localization of a recessive gene for North American Indian childhood cirrhosis to chromosome region 16q22--and identification of a shared haplotype. Am. J. Hum. Genet. 67: 222-228, 2000. [PubMed: 10820129] [Full Text: https://doi.org/10.1086/302993]
Chagnon, P., Michaud, J., Mitchell, G., Mercier, J., Marion, J.-F., Drouin, E., Rasquin-Weber, A., Hudson, T. J., Richter, A. A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis. Am. J. Hum. Genet. 71: 1443-1449, 2002. [PubMed: 12417987] [Full Text: https://doi.org/10.1086/344580]
Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536: 285-291, 2016. [PubMed: 27535533] [Full Text: https://doi.org/10.1038/nature19057]
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K., Rehm, H. L. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology. Genet. Med. 17: 405-424, 2015. [PubMed: 25741868] [Full Text: https://doi.org/10.1038/gim.2015.30]
Weber, A. M., Tuchweber, B., Yousef, I., Brochu, P., Turgeon, C., Gabbiani, G., Morin, C. L., Roy, C. C. Severe familial cholestasis in North American Indian children: a clinical model of microfilament dysfunction? Gastroenterology 81: 653-662, 1981. [PubMed: 6894906]