Monogenic Etiologies of Kidney Cysts in the Pediatric Population: An Observational Cohort Study

Abstract

Background: Pediatric kidney cysts may indicate an underlying genetic disorder, yet the full spectrum of causes remains incompletely defined. With advances in genetic testing enabling broader evaluation, this study assessed the diagnostic utility of comprehensive genetic testing in a broad pediatric cohort with kidney cysts and characterized the underlying etiological diversity.

Methods: This observational cohort study included <18-year-olds enrolled between January 2020 and June 2024 at a single tertiary center. Genetic testing used targeted multi-gene or custom curated exome/genome sequencing panels, with segregation analysis when available. Eligible participants had at least two cysts without family history, one cyst with positive family history, or enlarged echogenic kidneys on prenatal ultrasound; those with congenital anomalies of the kidney and urinary tract associated with cysts were excluded. Clinical presentation was categorized as symptomatic, incidental, prenatal, or family screening. Primary outcomes were diagnostic yield and distribution of pathogenic variants.

Results: Among 109 patients (median age 7.6 years, 53% female), genetic testing identified a definitive diagnosis in 81 of 100 tested patients (81%) from 72 families (79%; 14 disorders). PKD1 variants were most common (45%), while PKD2 accounted for 7%. Other causes included HNF1B or 17q12 deletions (13%), minor ADPKD genes (11%; GANAB, NEK8, IFT140), monoallelic-PKHD1 (3%), and biallelic PKHD1 (8%), while syndromic ciliopathy genes accounted for 5%. A positive family history strongly correlated with a genetic diagnosis (54% vs. 11%; p = 0.008). Patients without an identified genetic diagnosis more often had unilateral cysts (26% vs. 4%; p = 0.53). Diagnosis by clinical symptoms was the most genetically diverse category.

Conclusions: Comprehensive genetic testing in pediatric kidney cysts achieved high diagnostic yield in a selected cohort and identified diverse causes beyond major ADPKD/ARPKD genes, supporting early evaluation to improve diagnostic accuracy, inform prognosis, and guide management, even in the absence of family history.