Genotype and Phenotype in Children with ADPKD-Related Gene Variants

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Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder. However, clinical data on pediatric cases remain limited, and the childhood phenotype is not fully characterized. Methods: We retrospectively analyzed pediatric patients (≤18 years) in whom pathogenic variants in ADPKD-related genes were identified using a next-generation sequencing (NGS)-based kidney disease gene panel. Clinical information, including genotype, family history, age at diagnosis, indication for genetic testing, kidney phenotype, and extrarenal manifestations, was extracted from medical records. Estimated glomerular filtration rate (eGFR) was evaluated in patients aged ≥3 months using the Japanese equation for children. Results: Pathogenic variants were identified in 51 patients from 48 families: PKD1 in 88%, PKD2 in 10%, and GANAB in 2%. The median age at diagnosis was 6 years. The most common indication for genetic testing was prenatal or neonatal ultrasound (47%), followed by abnormal urinalysis, gross hematuria, and urinary tract infections (each 11%). A positive family history was noted in approximately half of the cases. Bilateral multiple kidney cysts were observed in 92% and unilateral cysts in 6%. Hypertension and hepatic cysts were found in 35% and 11%, respectively; no intracranial aneurysms were detected. Among PKD1 variants, 14 families had truncating variants, 12 had non-truncating variants, 9 had PKD1/TSC2 contiguous gene deletions, and 7 had biallelic PKD1 variants. Median age at diagnosis was 7.0, 3.0, 1.7, and 8.0 years, and median eGFR was 110, 117, 119, and 73 mL/min/1.73m2, respectively. Although there were no statistically significant differences in eGFR among PKD1 variant groups, 60% (3/5) of patients with biallelic PKD1 variants had eGFR <60 mL/min/1.73m2 at diagnosis. Conclusion: Although pediatric ADPKD has been considered clinically silent, nearly half of the patients in this study were diagnosed during the neonatal period, and most had bilateral multiple kidney cysts. While no clear genotype–phenotype correlation was observed in terms of kidney function among PKD1 variant types, biallelic PKD1 variants may be associated with early-onset kidney dysfunction.

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