Localization of a recessive gene for North American Indian childhood cirrhosis to chromosome region 16q22-and identification of a shared haplotype

Abstract

North American Indian childhood cirrhosis (NAIC, or CIRH1A) is an isolated nonsyndromic form of familial cholestasis reported in Ojibway-Cree children and young adults in northwestern Quebec. The pattern of transmission is consistent with an autosomal recessive mode of inheritance. To map the NAIC locus, we performed a genomewide scan on three DNA pools of samples from 13 patients, 16 unaffected siblings, and 22 parents from five families. Analysis of 333 highly polymorphic markers revealed 3 markers with apparent excess allele sharing among affected individuals. Additional mapping identified a chromosome 16q segment shared by all affected individuals. When the program FASTLINK/LINKAGE was used and a completely penetrant autosomal recessive mode of inheritance was assumed, a maximum LOD score of 4.44 was observed for a recombination fraction of 0, with marker D16S3067. A five-marker haplotype (D16S3067, D16S752, D16S2624, D16S3025, and D16S3106) spanning 4.9 cM was shared by all patients. These results provide significant evidence of linkage for a candidate gene on chromosome 16q22.

Figure 1

Pedigrees of five families with NAIC. Blackened symbols represent individuals with clinically and biochemically documented NAIC. An asterisk (*) indicates an individual whose DNA sample was genotyped. The identification prefix “N” denotes the initial 51 family members who provided DNA samples for the study; DNA samples from 7 additional NAIC patients (designated “9038,” “9039,” “9052,” “9106,” “9108,” “9133,” and “9134”) became available later and were included in the linkage and haplotype analyses. The number in a diamond-shaped symbol is the number of additional family members for whom DNA samples were not available.

Figure 2

ABI 377 electropherograms for six SSLPs, for three DNA pools (parents, unaffected siblings, and patients). D15S657 and D7S1804 are representative markers that have multiple peaks in all DNA pools, corresponding to distinguishable alleles. GATA10G07 appears to be monomorphic in all three DNA pools. Three markers (D16S2624, D8S1106, and D4S403) had a predominant peak in the DNA pool of affected children but differed by the presence of two or more peaks in the parent and unaffected-sibling pools.