Genetic diagnosis of autosomal dominant polycystic kidney disease: linkage analysis versus direct mutation analysis

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases and accounts for 2e5% of end-stage renal disease (ESRD) [1]. Mutations in 2 genes mainly cause ADPKD. The polycystic kidney disease 1 (PKD1) locus accounts for approximately 85% of the patients, and the polycystic kidney disease 2 (PKD2) locus accounts for approximately 15% of the patients [2]. The typical phenotype is progressive renal cyst development and enlargement leading to decreased renal function. ADPKD slowly develops over several decades, and disease progression to ESRD is highly variable according to genetic loci. The patients with PKD1 mutation have larger kidneys and earlier onset of ESRD than those with PKD2 mutation (mean age at ESRD, 53.4 vs. 72.7 years) [3,4]. The ability and demand for genetic testing are recently changing for several reasons [1]. First, technological advances in genome sequencing (targeted next-generation sequencing) have resulted in the development of automated highthroughput tests, which are getting cheaper. Second, genetic mutation is a key determinant of phenotype in ADPKD. Genetic and allelic effects mainly determine the progression of ADPKD. Third, the long and expensive treatment with new drugs to suppress the cyst growth might request for genetic tests. Genetic diagnosis could guide who will be benefited by the treatment. Fourth, presymptomatic testing in prenatal or younger at-risk individuals might be advocated in early treatment or familial planning. There are 2 methods for genetic testing: DNA linkage analysis and direct mutation screening. Linkage analysis detects excessive cosegregation of the putative alleles underlying a familial phenotype [5]. For many years, linkage analysis has been the primary tool used for genetic disease with familial aggregation. However, there are several limitations to linkage testing. Linkage analysis cannot be used if a family is small. A minimum of 4 affected family members' DNA in 2 generations is required. Linkage analysis is possible to determine the genetic loci, but information of pathogenic mutation cannot be obtained [6]. Direct mutation analysis is another genetic method used for ADPKD. It involves direct sequencing of the entire coding regions of both PKD1 and PKD2, including intron/exon boundaries. To date, more than 1,272 PKD1 and 202 PKD2 different pathologic mutations have been reported (http://pkdb.mayo. edu). The major limitation of direct mutation analysis is the