Prenatal‐Onset Autosomal Dominant Polycystic Kidney Disease: Clinical Spectrum and Genetic Complexity of a Pseudo‐Recessive Phenotype

OBJECTIVE: Renal cystic dysplasia represents a group of disorders involving primary cilia dysfunction. Autosomal dominant polycystic kidney disease (ADPKD) due to PKD1 pathogenic variants typically presents in adulthood; we investigated rare prenatal-onset cases to better understand their genetic basis and clinical implications. METHOD: We performed whole-genome sequencing in trio and long-read sequencing on seven prenatal ADPKD cases. Variant interpretation followed ACMG guidelines, with special consideration for hypomorphic alleles and long-read sequencing for haplotype resolution in some cases. RESULTS: Our study identified three novel hypomorphic PKD1 variants. Four families showed biallelic inheritance patterns, including one with two affected parents. Despite severe prenatal ultrasound findings, only one case required neonatal dialysis, and all cases lacked oligohydramnios. All other patients revealed no ESKD at the age of diagnosis. CONCLUSIONS: NGS analysis proves essential for diagnosis but requires comprehensive approaches to detect hypomorphic variants and underscores the necessity for comprehensive evaluation of hypomorphic alleles. Our findings demonstrate that prenatal detection does not necessarily predict rapid disease progression, offering new prognostic insights for severe ADPKD presentations that is extremely important for accurate genetic counseling. These results emphasize the need for functional studies of hypomorphic variants while providing a framework for clinical interpretation of early-onset ADPKD cases.