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 approximately 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 approximately 65% of patients have definite mutations with approximately 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.

Figure 1

Gene structure of PKD1 and PKD2 and protein structure of polycystin-1 and polycystin-2. a ∣ Gene and messenger RNA structure of PKD1 and PKD2. The 5′ end of PKD1 from exon 1 to 33 lies in a duplicated genomic region (light green) and the 3′ end of the gene is immediately adjacent (within ~60 bp) to the 3′ end of the tuberous sclerosis gene, TSC2. b ∣ Protein structures of polycystin-1 and polycystin-2. Details of the known domain structures of the polycystins are shown in the figure. Abbreviations: ER, endoplasmic reticulum; GPS, GPCR proteolytic site; LDL, low-density lipoprotein; PKD, polycystic kidney disease; TRP, transient receptor potential.

Figure 2

Summary of data from the ADPKD mutation database. a ∣ Classification and numbers of different variants found in PKD1 (top) and PKD2 (bottom) in the ADPKD mutation database. Changes that are probably pathogenic are classified into three groups depending on the likelihood that they are associated with disease. Many more neutral variants are found in PKD1 than in PKD2. b ∣ Classification and numbers of families affected by changes in PKD1 and PKD2 that are probably pathogenic. A greater number of missense changes are found in PKD1 than in PKD2, and a higher proportion of splicing variants are found in PKD2. Note that the numbers in panels a and b differ because panel a concerns the number of different variants and panel b concerns the number of affected families. Some mutations are found in more than one family.