Genetic and phenotypic aspects of autosomal recessive polycystic kidney disease in southern Israel

Background: Autosomal recessive polycystic kidney disease (ARPKD) is a severe renal disease. Kidneys and liver may be affected clinically but at a varying severity, ranging from a Potter-like syndrome, systemic hypertension and variable renal dysfunction to portal hypertension due to hepatic fibrosis. Most ARPKD cases are caused by mutations in the gene PKHD1. Specific mutations in patients from various ethnic backgrounds have been described, most cases being compound heterozygotes. The genotype-phenotype correlation has not been sufficiently studied. Objectives: a) Clinical characterization of ARPKD patients in Southern Israel. b) Establishment of a genetic method for prenatal diagnosis of the disease. Methods: Clinical data of all ARPKD cases diagnosed in our institution was retrospectively analyzed. DNA samples were collected from the patients, parents and siblings. Linkage analysis was used to verify individual genetic status. Results: Eighteen ARPKD patients from 7 extended Bedouin families were identified (perinatal manifestation = 9; neonatal = 2; infantile = 2; juvenile = 5). The family trees in all cases were highly suggestive of a founder effect, implying that affected individuals were very likely to harbor identical mutations on both ARPKD alleles. Inter- and intra-familial phenotypic variability was found in several families. Linkage analysis using polymorphic markers specific to the chromosome 6p-PKHD1 locus was established in our laboratory and was found to be reliable, thereby assisting in prenatal diagnosis in known ARPKD families. Conclusions: Phenotypic variability exists in ARPKD, even among families with supposedly homozygous mutations in the PKHD1 gene. We have established a reliable method for prenatal diagnosis of the disease by linkage analysis, thus enabling future diagnosis in families at risk.