Diagnostic Utility of Exome Sequencing Among Israeli Children With Kidney Failure

Yishay Ben-Moshe, Omer Shlomovitz, Danit Atias-Varon, Orly Haskin, Efrat Ben-Shalom, Hadas Shasha Lavsky, Oded Volovelsky, Shrikant Mane, Dror Ben-Ruby, Guy Chowers, Karl Skorecki, Yael Borovitz, Maayan Kagan, Nofar Mor, Yulia Khavkin, Shimrit Tzvi-Behr, Shirley Pollack, Moran Plonsky Toder, Michael Geylis, Aviad SchnappRachel Becker-Cohen, Irith Weissman, Ruth Schreiber, Miriam Davidovits, Yaacov Frishberg, Daniella Magen, Ortal Barel, Asaf Vivante*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2126-2135
Number of pages10
JournalKidney International Reports
Volume8
Issue number10
DOIs
StatePublished - Oct 2023

Keywords

  • ESKD
  • children
  • dialysis
  • exome sequencing
  • kidney failure
  • monogenic

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