Refinement of the critical region for MCKD1 by detection of transcontinental haplotype sharing

Background. Autosomal-dominant medullary cystic kidney disease type 1 (MCKD1) [OMIM 174000] is a hereditary nephropathy that leads to renal salt wasting and end-stage renal failure at a median age of 62 years. In a Welsh MCKD1 kindred we have recently demonstrated linkage to the MCKD1 locus on chromosome 1q23.1 and refined the critical MCKD1 region to <3.3 Mb. Methods. In order to refine the candidate gene region for MCKD1, high-resolution haplotype analysis in three large kindreds with MCKD1 was performed. Results. We report here on high-resolution haplotype analysis in this Welsh kindred, as well as in the Arizona kindred, which was used for the first definition of MCKD as a disease entity, and in a kindred from the Dutch/German border. We detected extensive haplotype sharing among all affected individuals of all three kindreds. Scrutinization of the genealogy of the Arizona kindred revealed an origin from Germany in the 17th century, thereby providing historical data for haplotype sharing by descent at the MCKD1 locus. Conclusion. Under the hypothesis of haplotype sharing by descent, we refined the critical genetic interval to <650 kb, thus enabling candidate gene analysis.