Diagnostic Utility of Exome Sequencing Among Israeli Children With Kidney Failure

Abstract

Introduction: Genetic etiologies are estimated to account for a large portion of chronic kidney diseases (CKD) in children. However, data are lacking regarding the true prevalence of monogenic etiologies stemming from an unselected population screen of children with advanced CKD.

Methods: We conducted a national multicenter prospective study of all Israeli pediatric dialysis units to provide comprehensive "real-world" evidence for the genetic basis of childhood kidney failure in Israel. We performed exome sequencing and assessed the genetic diagnostic yield.

Results: Between 2019 and 2022, we recruited approximately 88% (n = 79) of the children on dialysis from all 6 Israeli pediatric dialysis units. We identified genetic etiologies in 36 of 79 (45%) participants. The most common subgroup of diagnostic variants was in congenital anomalies of the kidney and urinary tract causing genes (e.g., EYA1, HNF1B, PAX2, COL4A1, and NFIA) which together explain 28% of all monogenic etiologies. This was followed by mutations in genes causing renal cystic ciliopathies (e.g., NPHP1, NPHP4, PKHD1, and BBS9), steroid-resistant nephrotic syndrome (e.g., LAGE3, NPHS1, NPHS2, LMX1B, and SMARCAL1) and tubulopathies (e.g., CTNS and AQP2). The genetic diagnostic yield was higher among Arabs compared to Jewish individuals (55% vs. 29%) and in children from consanguineous compared to nonconsanguineous families (63% vs. 29%). In 5 participants (14%) with genetic diagnoses, the molecular diagnosis did not correspond with the pre-exome diagnosis. Genetic diagnosis has a potential influence on clinical management in 27 of 36 participants (75%).

Conclusion: Exome sequencing in an unbiased Israeli nationwide dialysis-treated kidney failure pediatric cohort resulted in a genetic diagnostic yield of 45% and can often affect clinical decision making.

Keywords: ESKD; children; dialysis; exome sequencing; kidney failure; monogenic.

Graphical abstract

Figure 1

Diagnostic yield of exome sequencing in Israeli children on dialysis. In 36 (45%) participants (blue), we identified monogenic CKD-related diagnostic variants. For the 36 solved cases, the different genes of the diagnostic variants are grouped into subcategories and displayed on the right side. CAKUT, congenital anomalies of the kidney and the urinary tract; CKD, chronic kidney disease; SRNS, steroid-resistant nephrotic syndrome.

Figure 2

Proportion of monogenic CKD etiologies across different clinical categories. (a) Proportion of monogenic CKD across different etiology groups. Among patients with tubulopathies, nephrolithiasis-related kidney disease and renal cystic ciliopathies, the yield was very high ∼90% to 100% compared with lower yields of ∼17% to 30% among patients with glomerulopathy, CAKUT, and CKDu. One patient with kidney failure secondary to acute kidney injury (AKI) is not displayed in the left panel. (b) Proportion of monogenic CKD across different patient’s characteristics. CAKUT, congenital anomalies of the kidney and the urinary tract; CKD, chronic kidney disease; CKDu, CKD of unknown etiology; FHx, family history; SRNS, steroid-resistant nephrotic syndrome.