Genetic Markers Among the Israeli Druze Minority Population With End-Stage Kidney Disease

Omer Shlomovitz, Danit Atias-Varon, Dina Yagel, Ortal Barel, Hadas Shasha-Lavsky, Karl Skorecki, Aviva Eliyahu, Younes Bathish, Victor Frajewicki, Daniel Kushnir, Rinat Zaid, Tamar Paperna, Ayala Ofir, Marina Tchirkov, Kamal Hassan, Etty Kruzel, Khaled Khazim, Ronit Geron, Irit Weisman, Anaam HanutFarid Nakhoul, Yael Kenig-Kozlovsky, Gery Refael, Alon Antebi, Shimon Storch, Marcel Leiba, Maayan Kagan, Rachel Shukrun, Gidi Rechavi, Benjamin Dekel, Yishay Ben Moshe, Karin Weiss, Suheir Assady, Asaf Vivante*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale & Objective: Genetic etiologies have been identified among approximately 10% of adults with chronic kidney disease (CKD). However, data are lacking regarding the prevalence of monogenic etiologies especially among members of minority groups. This study characterized the genetic markers among members of an Israeli minority group with end-stage kidney disease (ESKD). Study Design: A national-multicenter cross-sectional study of Israeli Druze patients (an Arabic-speaking Near-Eastern transnational population isolate) who are receiving maintenance dialysis for ESKD. All study participants underwent exome sequencing. Setting & Participants: We recruited 94 adults with ESKD, comprising 97% of the total 97 Druze individuals throughout Israel being treated with dialysis during the study period. Predictors: Demographics and clinical characteristics of kidney disease. Outcome: Genetic markers. Analytical Approach: Whole-exome sequencing and the relationship of markers to clinical phenotypes. Results: We identified genetic etiologies in 17 of 94 participants (18%). None had a previous molecular diagnosis. A novel, population-specific, WDR19 homozygous pathogenic variant (p.Cys293Tyr) was the most common genetic finding. Other monogenic etiologies included PKD1, PKD2, type IV collagen mutations, and monogenic forms of noncommunicable diseases. The pre-exome clinical diagnosis corresponded to the final molecular diagnosis in fewer than half of the participants. Limitations: This study was limited to Druze individuals, so its generalizability may be limited. Conclusions: Exome sequencing identified a genetic diagnosis in approximately 18% of Druze individuals with ESKD. These results support conducting genetic analyses in minority populations with high rates of CKD and for whom phenotypic disease specificity may be low. Plain-Language Summary: Chronic kidney disease (CKD) affects many people worldwide and has multiple genetic causes. However, there is limited information on the prevalence of genetic etiologies, especially among minority populations. Our national-multicenter study focused on Israeli Druze patients. Using exome-sequencing, we identified previously undetected genetic causes in nearly 20% of patients, including a new and population-specific WDR19 homozygous pathogenic variant. This mutation has not been previously described; it is extremely rare globally but is common among the Druze, which highlights the importance of studying minority populations with high rates of CKD. Our findings provide insights into the genetic basis of end-stage kidney disease in the Israeli Druze, expand the WDR19 phenotypic spectrum, and emphasize the potential value of genetic testing in such populations.

Original languageEnglish
Pages (from-to)183-195
Number of pages13
JournalAmerican Journal of Kidney Diseases
Volume83
Issue number2
DOIs
StatePublished - Feb 2024

Funding

FundersFunder number
European Renal Association
StG ERC101040267-GeneCKD
Israel Science Foundation2773/19

    Keywords

    • CKD
    • Ciliopathy
    • Druze
    • ESKD
    • WDR19
    • exome sequencing
    • genetic
    • minority
    • monogenic
    • nephronophtisis-13

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