Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease.

Purpose To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010-2020). Methods All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation sequencing panel of 15 additional cystic genes including PKHD1 and HNF1B. Two patients underwent exome or genome sequencing. Results Likely causative PKD1 or PKD2 variants were detected in 30 infants with PKD-VEO, 16 of whom presented in utero. Twenty-one of 30 (70%) had two variants with biallelic in trans inheritance confirmed in 16/21, 1 infant had biallelic PKD2 variants, and 2 infants had digenic PKD1/PKD2 variants. There was no known family history of ADPKD in 13 families (43%) and a de novo pathogenic variant was confirmed in 6 families (23%). Conclusion We report a high prevalence of hypomorphic PKD1 variants and likely biallelic disease in infants presenting with PKD-VEO with major implications for reproductive counseling. The diagnostic interpretation and reporting of these variants however remains challenging using current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Association of Clinical Genetic Science (ACGS) variant classification guidelines in PKD-VEO and other diseases affected by similar variants with incomplete penetrance.