Identification of a locus for autosomal dominant polycystic liver disease, on chromosome 19p13.2-13.1

Abstract

Polycystic liver disease (PCLD) is characterized by the growth of fluid-filled cysts of biliary epithelial origin in the liver. Although the disease is often asymptomatic, it can, when severe, lead to complications requiring surgical therapy. PCLD is most often associated with autosomal dominant polycystic kidney disease (ADPKD); however, families with an isolated polycystic liver phenotype without kidney involvement have been described. The clinical presentation and histological features of polycystic liver disease in the presence or absence of ADPKD are indistinguishable, raising the possibility that the pathogenetic mechanisms in the diseases are interrelated. We ascertained two large families with polycystic liver disease without kidney cysts and performed a genomewide scan for genetic linkage. A causative gene, PCLD, was mapped to chromosome 19p13.2-13.1, with a maximum LOD score of 10.3. Haplotype analysis refined the PCLD interval to 12.5 cM flanked by D19S586/D19S583 and D19S593/D19S579. The discovery of genetic linkage will facilitate diagnosis and study of this underdiagnosed disease entity. Identification of PCLD will be instrumental to an understanding of the pathogenesis of cyst formation in the liver in isolated PCLD and in ADPKD.

Figure 1

Pedigrees of families 1 and 2, which have isolated PCLD, and associated chromosome 19p haplotypes. The black bars denote the haplotypes at informative markers segregating with the disease phenotype. Black symbols denote affected individuals; white symbols containing an “N” denote unaffected individuals; white symbols containing cross hairs denote individual whose affection status is unknown; white symbols not containing any of the aforementioned items denote individuals not at risk. The numbers to the upper right of the symbols are the ages (in years) at ultrasound examination. The marker order is given to the left of each generation in the pedigrees; intermarker genetic distances are shown in figure 3. Question marks denote unknown alleles. Individuals II:5, III:16, III:17, and III:18 in family 1 and individuals II:6, II:13, III:4, and III:14 in family 2 define the centromeric boundary of the disease interval at D19S593/579. Individuals II:1 and III:19 in family 1 define the telomeric boundary at D19S406; III:3 also shows recombination between PCLD and D19S586.

Figure 2

Computerized tomograms of the abdomen, illustrating extensive PCLD in the absence of renal cysts in (A panels) individual III:7 in family 1 and (B panels) individual III:11 in family 2.

Figure 3

Genetic map of markers used in this study. Distances (in cM) were obtained from the Marshfield sex-averaged map. D19S394 is not genetically mapped but, rather, on the basis of the Chromosome 19–p Arm Metric Physical Map (Lawrence Livermore Laboratory) maps 1 Mb centromeric to D19S586p. Markers defining the PCLD genetic interval are in boldface.

Figure 4

Multipoint analysis with 10 chromosome 19 markers. The maximum LOD score is obtained with D19S221/D19S558, and the 3-LOD support interval is between D19S406 and D19S593/D19S579.