Evolving role of genetic testing for the clinical management of autosomal dominant polycystic kidney disease

Abstract

<jats:title>Abstract</jats:title> <jats:p>Autosomal dominant polycystic kidney disease (ADPKD) is caused primarily by mutations of two genes, PKD1 and PKD2. In the presence of a positive family history of ADPKD, genetic testing is currently seldom indicated as the diagnosis is mostly based on imaging studies using well-established criteria. Moreover, PKD1 mutation screening is technically challenging due to its large size, complexity (i.e. presence of six pseudogenes with high levels of DNA sequence similarity) and extensive allelic heterogeneity. Despite these limitations, recent studies have delineated a strong genotype–phenotype correlation in ADPKD and begun to unravel the role of genetics underlying cases with atypical phenotypes. Furthermore, adaptation of next-generation sequencing (NGS) to clinical PKD genetic testing will provide a high-throughput, accurate and comprehensive screen of multiple cystic disease and modifier genes at a reduced cost. In this review, we discuss the evolving indications of genetic testing in ADPKD and how NGS-based screening promises to yield clinically important prognostic information for both typical as well as unusual genetic (e.g. allelic or genic interactions, somatic mosaicism, cystic kidney disease modifiers) cases to advance personalized medicine in the era of novel therapeutics for ADPKD.</jats:p>

Insights into Autosomal Dominant Polycystic Kidney Disease from Genetic Studies

“…In this setting, the differential diagnosis should also include PKD due to mutations in DNAJB11 or ALG9, thin basement membrane disease (due to a heterozygous COL4A3 or COL4A4 mutation), or apoL1 kidney disease in a Black patient with proteinuria (49). Table 1 provides a list of genes that can lead to cystic kidney diseases when mutated (49). Of note, syndromic manifestations in these disorders may often provide clues to their diagnosis.…”

“…For example, the presence of gout and hyperuricemia is suggestive of ADTKD associated with uromodulin mutations, whereas the presence of maturity-onset diabetes of the young and/or genitourinary tract malformation is suggestive of ADTKD associated with HNF1B mutations. Other rare forms of PKD with distinctive syndromic features include von Hippel-Lindau disease; nephronophthisis; X-linked dominant orofaciodigital syndrome; hereditary angiopathy, nephropathy, aneurysms, and muscle cramps syndrome; and hyperinsulinemic hypoglycemia with PKD (49). By comprehensively screening a list of known and potential cystic disease genes, genetic testing with high-throughput sequencing is expected to improve diagnostic accuracy in patients with cystic kidney disease.…”

International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people

“…In adults, genetic testing for ADPKD is usually not done because of the clearly established imaging diagnostic criteria and the technical challenges of sequencing PKD1. However, knowledge about genotype-phenotype correlations is increasing, as is the need for more accurate estimation of prognosis in view of novel therapies 49 . Both very-early-onset ADPKD and rapidly progressive disease may be due to unusual genetic constellations, such as biallelic mutations (homozygous, compound heterozygous or digenic) with at least one weak PKD1 or PKD2 hypomorphic allele 5,[50][51][52] .…”

Molecular Structure of the PKD Protein Complex Finally Solved

“…Indications for gene testing include to screen young kidney donors from ADPKD families, perform preimplantation genetic diagnosis, and establish an ADPKD diagnosis when the clinical picture is not clear. 24 However, the large number of amino acid variants of unknown significance, particularly in PKD1, has hampered the utility of gene testing. 1,24 It is sometimes difficult to predict what change, if any, an amino acid substitution will have on the protein's function.…”

“…24 However, the large number of amino acid variants of unknown significance, particularly in PKD1, has hampered the utility of gene testing. 1,24 It is sometimes difficult to predict what change, if any, an amino acid substitution will have on the protein's function. With this new PC1/PC2 structure, we should have a better template on which to map variants, which will allow more accurate prediction of their pathogenicity.…”