Recommendations

1. Based on existing data, genetic testing is not necessary for selecting treatment options for patients with a confirmed diagnosis of ADPKD.
2. If genetic testing is to be done, it should be done by a Clinical Laboratory Improvement Amendments (CLIA)-certified center and interpreted by those familiar with ADPKD genetics.

Genetic Testing in ADPKD

ADPKD is genetically heterogeneous with 2 genes identified: PKD1 (chromosome 16p13.3) and PKD2 (4q21).¹⁰ Mutations in the PKD1 gene occur in 85% to 90% of cases of ADPKD, whereas mutations in the PKD2 gene account for the remainder of cases.^11,12 The PKD1 and PKD2 genes encode 2 proteins, polycystin-1 and polycystin-2, that constitute the transient receptor potential polycystin subfamily of transient receptor potential channels.¹⁰ Genic, allelic, and gene modifier effects contribute to the high phenotypic variability of ADPKD, and truncating PKD1 mutations are associated with more severe disease and earlier decline in kidney function compared 0with nontruncating PKD1 mutations.¹³ According to the PKD Foundation of Canada, there are currently 2323 known mutations in the PKD1 gene and 278 known mutations in the PKD2 gene (Autosomal Dominant Polycystic Kidney Disease Mutation Database [PKDB], http://pkdb.mayo.edu/).

Genetic testing for ADPKD can be carried out using DNA linkage analysis, gene-based mutation screening (also referred to as Sanger sequencing), or, in the near future, nextgeneration sequencing (NGS). Up-to-date information regarding laboratories currently offering genetic testing for ADPKD can be obtained from GeneTests (www.genetests.org), a valuable web-based resource funded by the National Institutes of Health.¹⁴ The Web site provides a comprehensive list of academic and commercial facilities worldwide that offer testing for PKD1 or PKD2 mutations on a clinical or research basis.

DNA linkage analysis seeks to identify the presence of a segment of the chromosome at either the PKD1 or PKD2 locus that completely segregates with the disease. Thus, there is no need to identify the exact ADPKD mutation as the presence of these markers and not the mutations themselves is being tracked. There are currently 15 microsatellite markers for PKD1 and 8 for PKD2.¹⁵ DNA linkage analysis, however, is useful only in familial cases and requires a large family with at least 4 affected members in at least 2 generations, with radiological studies in both affected and unaffected individuals, for conclusive results. Results must be interpreted with caution if there are de novo mutations, mosaicisms, and hypomorphic alleles.

Gene-based mutation screening is the most commonly used method for genetic diagnosis of ADPKD. This approach seeks to identify the exact mutation in the PKD1 and PKD2 genes. Because most mutations are unique to a single family with no clear “hot spots,” exon-by-exon screening of these genes is necessary to ensure high sensitivity in detecting disease-causing mutations in PKD1 and PKD2.¹⁶ Challenges of gene-based mutation screening include the difficulty in differentiating disease-causing missense mutations from benign variants, the detection of a definitive mutation in no more than 65% to 75% of patients tested, and the lack of a confirmed pathogenic mutation in approximately 8% of patients with ADPKD.¹³

NGS, also known as high-throughput sequencing, refers to a number of different modern sequencing technologies that can sequence millions of small fragments of DNA in parallel and use bioinformatic analyses to piece together these fragments and provide accurate data on genetic mutations.¹⁷ Compared with gene-based mutation screening, NGS offers the benefits of high fidelity, high throughput, and high speed.¹⁸ NGS was validated in a cohort of 25 patients who had previously undergone genetic testing using gene-based mutation screening.¹⁹ NGS identified 250 genetic variants in the PKD1 and PKD2 genes, including all 16 pathogenic mutations and 3 novel mutations that gene-based mutation screening did not identify. In this study, NGS showed sensitivity of 99.2% and specificity of 99.9%, with cost and turnaround time reduced by approximately 70% compared with gene-based mutation screening sequencing.

Although genetic testing for ADPKD mutations is indicated in some patients, it is not indicated for all patients. Genetic testing is not needed when a firm positive or negative diagnosis can be made by imaging alone or, as in the case of a patient with suspected ADPKD, when a diagnosis can be made based on the imaging results of the patient’s parents or based on the presence of extrarenal manifestations. Genetic testing should be considered in potential living related donors to confirm the absence of any mutations for ADPKD, in patients without a family history of ADPKD (especially if radiographic presentation is atypical, if renal disease is mild, if extrarenal symptoms are atypical, or if prognostic information is required), in families with atypical radiographic patterns of kidney cysts to possibly exclude other cystic kidney diseases, in families affected by early-onset polycystic disease, and in patients who want a prenatal or preimplantation diagnosis.^15,20

Family history can be highly predictive of the genetic mutation.²¹ A family history of having at least one family member with early-onset ESRD ≤55 to 58 years of age has a positive predictive value (PPV) of 100% for the presence of a mutation in the PKD1 gene. In contrast, a family history of having at least one family member who remained renal sufficient or developed ESRD ≥68 to 70 years of age had a PPV of 100% for a mutation in the PKD2 gene. Applying these 2 criteria can correctly predict the PKD1 or PKD2 mutation in approximately 75% of cases.