#5958 Value of Exome Sequencing “First” for Autosomal Dominant Polycystic Kidney Disease

Abstract

Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common Mendelian kidney diseases, that can progress to end-stage kidney failure. Pathological variants in PKD1 or PKD2 genes are found in about 78% and 15% respectively. Additional variants in genes such as GANAB, DNAJB11, and ALG8/5 have been identified in ADPKD. The sequencing of PKD1 by short read sequencing technics with exome capture such as Exome sequencing (ES) has been describe as technically challenging given 6 pseudogenes with more than 98% homology in PKD1 exonic regions 1 to 33. Moreover, the presence of repeated motifs and GC-rich in PKD1/2 add difficulties. We study the relevance of exome sequencing (ES) “first-hand” during autosomal dominant polycystic kidney disease. Method ES was performed in 684 unrelated adult patients with kidney disease from the department of Nephrology of Sorbonne University, Paris, France. Genomic DNA was extracted and exonic coding regions (37 megabases) were enriched with the Twist Human Core Exome kit, and paired-end sequenced on NextSeq500 (Illumina) machine. Sequences were analyzed with in-house and the SeqOne v1.3,2019 pipelines according to GATK4 best practices. If necessary, co-segregation of pathological variants was studied by Sanger sequencing in relatives. Results Of the 684 patients, 143 had renal cysts. Pathogenic or probably pathogenic variations in the PKD1, PKD2, and DNAJB11 genes have been identified in 26 patients, all with cystic disease; with respectively 17 variants in PKD1, 6 variants in PKD2 and 3 variants in DNAJB11. In this cohort, 18.2% of the 17 pathogenic variants are reported in PKD1, and 14 (82%) are included in exons 1 to 33. All variants were eventually confirmed by Sanger sequencing without false positive. Moreover, in 5 of the 26 patients diagnosed (19%), meaningful additional genetic data have been found, falling either in CFTR, DHCR7, HFE, F8, or ACTA2 gene. Conclusion ES highlights PKD1 and PKD2 pathogenic variants detection without false positive. This strategy allowed us to provide appropriate genetic counseling (CFTR, DHCR7), as management of yet unexpected additional genetic diseases that can affect ADPKD (F8, HFE, and ACTA2) phenotype. Given these preliminary data, ES appears effective for PKD1/PKD2 variant detection, providing additional information for ADPKD management in 20% of cases.