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Diagnostic Utility of Exome Sequencing Among Israeli Children With Kidney Failure
Yishay Ben-Moshe1,2, Omer Shlomovitz1,2, Danit Atias-Varon1,2,3
1Department of Pediatrics B, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel.
Insights
Genetic testing identified the cause of kidney failure in 45% of Israeli children on dialysis. This genetic diagnosis significantly impacts clinical management and decision-making for affected pediatric patients.
Area of Science:
- Pediatric Nephrology
- Medical Genetics
- Genomic Medicine
Background:
- Genetic factors are significant contributors to pediatric chronic kidney diseases (CKD).
- Limited data exist on the prevalence of monogenic causes in unselected pediatric CKD populations.
Purpose of the Study:
- To determine the genetic basis of kidney failure in a nationwide cohort of Israeli children undergoing dialysis.
- To assess the diagnostic yield of exome sequencing in this population.
Main Methods:
- A national, multicenter, prospective study involving pediatric dialysis units across Israel.
- Exome sequencing was performed on 79 children with advanced CKD.
- Genetic diagnostic yield and its correlation with clinical factors were assessed.
Main Results:
- Genetic etiologies were identified in 45% (36/79) of participants.
- Congenital anomalies of the kidney and urinary tract genes were the most common subgroup.
- Higher diagnostic yields were observed in Arab children and those from consanguineous families.
- Molecular diagnoses altered clinical management in 75% of genetically diagnosed cases.
Conclusions:
- Exome sequencing provides a high genetic diagnostic yield in a nationwide cohort of pediatric dialysis patients.
- Genetic diagnoses significantly influence clinical decision-making and management strategies in childhood kidney failure.
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.
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