The Importance of Familial Co-segregation in the Classification of a Novel PKD1 Variant Associated With Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a highly penetrant and clinically recognizable disorder, characterized by the presence of multiple bilateral kidney cysts. Variants in the PKD1 or PKD2 genes cause approximately 90% of cases, with the remaining 10% unresolved or caused by variants in other loci. This study demonstrates the utility of segregation studies for classifying genetic variants, as applied to a family with severe ADPKD and a novel PKD1 missense variant. A large family with multiple ADPKD patients is described. Genetic testing was performed using Sanger sequencing (PKD1 and PKD2) or NGS panel (PKD1, PKD2, and PKHD1 genes). CNV were excluded using MLPA (PKD1, PKD2, and PKHD1 genes). Variants were classified using the 2015 ACMG-AMP guidelines, and the full likelihood Bayes factor (FLB) was computed with the "segregatr" R-package (Version 0.3.0). The index patient and 13 family members across three generations had ultrasonographic confirmation of typical and progressive ADPKD. Preimplantation genetic testing (PGT) was requested, requiring molecular confirmation. The heterozygous PKD1 VUS c.8999G>C p.(Arg3000Pro) was identified in four affected patients and excluded in one unaffected patient. The FLB is 96.8, which, according to Jarvik and Browning's criteria, reclassified the variant as likely pathogenic. This classification aligned with ClinGen's 2024 recommendations and justified the PGT request. This family is clinically suggestive of PKD1-related ADPKD and shares one VUS in PKD1. FLB calculation enabled a rapid reclassification of the variant, demonstrating the value of segregation studies and accurate clinical phenotyping in genetic variant annotation.