Review of genetic testing in kidney disease patients: Diagnostic yield of single nucleotide variants and copy number variations evaluated across and within kidney phenotype groups

Abstract

Genetic kidney disease comprises a diverse group of disorders. These can roughly be divided in the phenotype groups congenital anomalies of the kidney and urinary tract, ciliopathies, glomerulopathies, stone disorders, tubulointerstitial kidney disease, and tubulopathies. Many etiologies can lead to chronic kidney disease that can progress to end-stage kidney disease. Despite each individual disease being rare, together these genetic disorders account for a large proportion of kidney disease cases. With the introduction of massively parallel sequencing, genetic testing has become more accessible, but a comprehensive analysis of the diagnostic yield is lacking. This review gives an overview of the diagnostic yield of genetic testing across and within the full range of kidney disease phenotypes through a systematic literature search that resulted in 115 included articles. Patient, test, and cohort characteristics that can influence the diagnostic yield are highlighted. Detection of copy number variations and their contribution to the diagnostic yield is described for all phenotype groups. Also, the impact of a genetic diagnosis for a patient and family members, which can be diagnostic, therapeutic, and prognostic, is shown through the included articles. This review will allow clinicians to estimate an a priori probability of finding a genetic cause for the kidney disease in their patients.

The role of genomic disorders in chronic kidney failure of undetermined aetiology ≤50 years

“…Whole-exome and whole-genome sequencing is gradually replacing traditional microarray-based methods for CNV screening and becoming first-tier screening tests as they allow for simultaneous detection of both CNVs as well as sequence variants, producing an overall higher diagnostic yield [ 18 ] and a cost-saving screening strategy [ 19 ]. However, there is a discrepancy between CNVs detected by microarray versus whole-exome/whole-genome sequencing, as the latter is often restricted to CNVs containing specific genes of interest.…”

Monogenic Kidney Diseases in Kidney Transplantation

“…A diagnostic yield was extrapolated ranging from 12.5% to 24.6%. 8 The authors report that positive family history, consanguinity, extrarenal features, and young age of onset of ESKD positively influenced the diagnostic yield. 8 However, it is important to state that ESKD onset at adult age should not prevent from pursuing a genetic diagnosis because typical childhood-onset diseases can be diagnosed at adult age.…”

“… 8 The authors report that positive family history, consanguinity, extrarenal features, and young age of onset of ESKD positively influenced the diagnostic yield. 8 However, it is important to state that ESKD onset at adult age should not prevent from pursuing a genetic diagnosis because typical childhood-onset diseases can be diagnosed at adult age. A prominent example is the rather common recurrent 290kb NPHP1 deletion that was detected in homozygous state in 0.5% of an adult cohort of 5606 patients with ESKDs.…”

GeNepher data- and biobank for patients with (suspected) genetic kidney disease: rationale, design and status update

“…A substantial proportion of patients with CKD has an (undiscovered) monogenic cause. [3,4] The timely identi cation of a potential genetic etiology in CKD patients has profound implications 1) for diagnosis and subsequent care, including personalized treatment and (extra-renal) follow-up, 2) for family members (e.g. in presymptomatic testing and family donation) and 3) for lifecycle medical care, for instance reproductive options (e.g.…”

“…preimplantation genetic diagnosis) and pregnancy care. [4,5] Having a genetic diagnosis can also end or prevent a "diagnostic odyssey" that is often invasive, time consuming and distressing. Additionally, genetic strati cation in clinical trials can prevent exposure to unnecessary risks and reduce confounders.…”