Monogenic Etiologies of Pediatric PKD: A Prospective Study

Background: Pediatric polycystic kidney disease (PKD) and ciliopathies show significant genetic diversity. ADPKD in children is typically linked to PKD1 and PKD2, however emerging adult data suggest a broader spectrum. This study assesses next-generation sequencing (NGS) to enhance diagnostic accuracy in pediatric PKD. Methods: This prospective cohort study (Jan 2020 to Jun 2024), included patients (pts) with ≥2 kidney cysts regardless of laterality and without a PKD family history, or ≥1 cyst with a confirmed PKD family history; pts with multicystic dysplastic kidneys were excluded. Data were obtained from medical records, and genetic testing was done using NGS PKD panels or custom curated kidney gene exome/genome panels, with family segregation analysis when available. Results: We evaluated 109 children (53% female, median age 7.6 years) from 99 families. Genetic testing was completed for 101 pts from 92 families, identifying pathogenic or likely pathogenic variants in 82 pts (81%) and 73 families (79%). Positive PKD family history and younger age of diagnosis were significantly higher in the genetically resolved group (P<0.05). Gene-specific variant frequencies identified among genetically resolved families are shown in Figure 1A. ADPKD genes accounted for 66% of the total, with PKD1 the most common (45%), but 4 minor ADPKD genes represented 10 families (14%). Eight percent of families were likely ARPKD-PKHD1, but HNF1B/17q12del accounted for a larger proportion (13%). Recessive, syndromic ciliopathies were responsible for just 5% of the resolved families. Pts’ initial presentations were classified into four categories: clinical symptoms, incidental finding, prenatal US detection, and family screening, and the variants detected for each category are shown in Figure 1B, with clinical symptoms the most genetically diverse. Conclusion: NGS-based testing offers a high and diverse diagnostic yield in pediatric PKD, revealing genetic causes of ADPKD beyond PKD1/PKD2. Broad testing is essential to obtain an accurate diagnosis, informing prognosis, and guide personalized care Funding: NIDDK Support