Genetics-first approach improves diagnostics of ESKD patients <50 years old

Abstract

Background Often only CKD patients with high likelihood of genetic disease are offered genetic testing. Early genetic testing could obviate the need for kidney biopsies, allowing for adequate prognostication and treatment. To test the viability of a ‘genetics first’ approach for CKD, we performed genetic testing in a group of kidney transplant recipients <50 years, irrespective of cause of transplant. Methods From a cohort of 273 transplant patients, we selected 110 that were in care in the UMC Utrecht, had DNA available and were without clear-cut non-genetic disease. Forty patients had been diagnosed with a genetic disease prior to enrollment, in 70 patients we performed a whole exome sequencing based 379 gene panel analysis. Results Genetic analysis yielded a diagnosis in 51%. Extrapolated to the 273 patient cohort, who did not all fit the inclusion criteria, the diagnostic yield was still 21%. Retrospectively, in 43% of biopsied patients the kidney biopsy would not have had added diagnostic value if genetic testing had been performed as a first tier diagnostic. Conclusions Burden of monogenic disease in transplant patients with ESKD of any cause prior to the age of 50 is between 21 and 51%. Early genetic testing can provide a non-invasive diagnostic, impacting prognostication and treatment and obviating the need for an invasive biopsy. We conclude that in patients who one expects to develop ESKD prior to the age of 50, genetic testing should be considered as first mode of diagnostics.

Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT

“…Adult cohorts previously studied using ES to a significant extent involved indistinct phenotypes, such as CKD of unknown cause, which to their nature harbor a higher likelihood of being caused by nonmonogenic conditions. 25,26,35 In a study from our group, in which ES was applied to adults with CKD from 114 families, CAKUT was found to be the underlying disease in 12% and thus was the most frequent cause. 24 Reverse phenotyping helps discern likely causative variants from inconclusive findings Analysis of ES data yielded a high number of likely deleterious variants in genes previously reported to cause syndromes with facultative CAKUT in families with a priori isolated CAKUT (Figure 1A).…”

Genetic testing in the diagnosis of chronic kidney disease: recommendations for clinical practice

“…Since features attributable to an underlying genetic diagnosis were not recognized prior to the genetic analysis in many patients with CKD of unknown origin, it seems appropriate to perform a genetic test in patients with severe CKD/ESKD and onset before the age of 50 years in whom a clear-cut non-genetic diagnosis (e.g. acute nephrotoxicity, diabetic nephropathy and infectious nephropathy) has been excluded [ 116 ]. Although there are rare cases of patients >50 years of age with adult-onset CKD in whom a genetic diagnosis was identified, the a priori chance of a genetic diagnosis in these older CKD patients seems extremely low and does not yet warrant genetic testing unless there is a clear family history [ 117 ].…”

Emerging Role of Clinical Genetics in CKD

“…Among those who received a kidney biopsy for diagnosis of CKD prior to study enrollment, biopsy results would have provided no additional diagnostic value for 43% of patients if genetic testing had been performed first. 86…”