Molecular diagnostics for autosomal dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common nephropathy caused by mutations in either PKD1 or PKD2. Mutations in PKD1 account for ~85% of cases and cause more severe disease than mutations in PKD2. Diagnosis of ADPKD before the onset of symptoms is usually performed using renal imaging by either ultrasonography, CT or MRI. In general, these modalities are reliable for the diagnosis of ADPKD in older individuals. However, molecular testing can be valuable when a definite diagnosis is required in young individuals, in individuals with a negative family history of ADPKD, and to facilitate preimplantation genetic diagnosis. Although linkage-based diagnostic approaches are feasible in large families, direct mutation screening is generally more applicable. As ADPKD displays a high level of allelic heterogeneity, complete screening of both genes is required. Consequently, such screening approaches are expensive. Screening of individuals with ADPKD detects mutations in up to 91% of cases. However, only ~65% of patients have definite mutations with ~26% having nondefinite changes that require further evaluation. Collation of known variants in the ADPKD mutation database and systematic scoring of nondefinite variants is increasing the diagnostic value of molecular screening. Genic information can be of prognostic value and recent investigation of hypomorphic PKD1 alleles suggests that allelic information may also be valuable in some atypical cases. In the future, when effective therapies are developed for ADPKD, molecular testing may become increasingly widespread. Rapid developments in DNA sequencing may also revolutionize testing.

Mutations in Multiple PKD Genes May Explain Early and Severe Polycystic Kidney Disease

“…The ADPKD and ARPKD mutation databases were used as a source of information about known PKD1, PKD2, and PKHD1 variants. 26,27 Scoring of likely mutations was performed as described previously 28 using a multisequence alignment of orthologs and different bioinformatic algorithms (Supplemental Table 1). The clinical and genetic data of all of the families discussed in this study are given in Supplemental Table 2.…”

Polycystic Kidney Disease and Cancer after Renal Transplantation

“…4 ADPKD is a result of mutations in one of two genes: PKD1 and PKD2. 1,5,6 These genes are widely expressed in many tissues, consistent with the multiorgan pathology characterizing ADPKD. A key factor in cyst formation and enlargement in ADPKD is the abnormal proliferation of cyst epithelial cells in a cell-autonomous manner.…”

Identification of Gene Mutations in Autosomal Dominant Polycystic Kidney Disease through Targeted Resequencing

“…3 Molecular testing also plays a role in the evaluation of potential living related kidney donors with doubtful imaging data, in individuals with a negative family history, and in cases of early onset ADPKD. 12 Furthermore, mutation characterization of clinical trials cohorts 3 provides genetic stratification for the evaluation of such trials. 13 The 59 two-thirds of the PKD1 gene (exons 1-32) is duplicated six times on chromosome 16 within six pseudogenes (PKD1P1-P6).…”