The Common PKD1 p.(Ile3167Phe) Variant Is Hypomorphic and Associated with Very Early Onset, Biallelic Polycystic Kidney Disease

Biallelic PKD1 variants, including hypomorphic can cause very early onset polycystic kidney disease (VEO-PKD). A family with unexplained recurrent VEO-PKD and neonatal demise in one dizygotic twin was referred for clinical testing. Further individuals the putative variant, p.(Ile3167Phe), were identified from UK 100,000 genomes project (100 K), Biobank (UKBB), a review of literature. We likely pathogenic missense paternal variant unaffected mother deceased but only surviving twin. Analysis 100 K cases second two siblings similar biallelic inheritance who presented at birth reached failure their teens unlike other affected relatives. Finally, survey 618 UKBB confirmed that adult patients monoallelic p.(Ile3167Phe) had normal function. Our data reveals is most common neutral heterozygosity associated when inherited trans variant. Care should be taken to ensure it not automatically filtered sequence VEO cases.