Arch Iran Med. September 2022;25(9):600-608 Original Article Targeted Next Generation Sequencing Revealed Novel Variants in the PKD1 and PKD2 Genes of Iranian Patients with Autosomal Dominant Polycystic Kidney Disease Maryam Hosseinpour, MSc 1# ; Fariba Ardalani, MSc 1# ; Marzieh Mohseni, PhD 1 ; Maryam Beheshtian, MD, MPH, PhD 1 ; Sanaz Arzhangi, MSc 1 ; Shahrzad Ossareh, MD 2 ; Hossein Najmabadi, PhD 1 ; Ali Nobakht, MD 3 ; Kimia Kahrizi, MD 1* ; Behrooz Broumand, MD 4* 1 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran 2 Division of Nephrology, Department of Medicine, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran 3 Department of Nephrology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran 4 Pars Advanced and Minimally Invasive Medical Manners Research Center, Pars Hospital, Tehran, Iran # Contributed equally as first authors Received: January 17, 2022, Accepted: April 10, 2021, ePublished: September 1, 2022 Abstract Background: Autosomal dominant polycystic kidney disease (ADPKD), one of the common inherited disorders in humans, is characterized by the development and enlargement of renal cysts, often leading to end-stage renal disease (ESRD). In this study, Iranian ADPKD families were subjected to high-throughput DNA sequencing to find potential causative variants facilitating the way toward risk assessment and targeted therapy. Methods: Our protocol was based on the targeted next generation sequencing (NGS) panel previously developed in our center comprising 12 genes involved in PKD. This panel has been applied to investigate the genetic causes of 32 patients with a clinical suspicion of ADPKD. Results: We identified a total of 31 variants for 32 individuals, two of which were each detected in two individuals. Twenty-seven out of 31 detected variants were interpreted as pathogenic/likely pathogenic and the remaining 4 of uncertain significance with a molecular diagnostic success rate of 87.5%. Among these variants, 25 PKD1/2 pathogenic/likely pathogenic variants were detected in 32 index patients (78.1%), and variants of uncertain significance in four individuals (12.5% in PKD1/2). The majority of variants was identified in PKD1 (74.2%). Autosomal recessive PKD was identified in one patient, indicating the similarities between recessive and dominant PKD. In concordance with earlier studies, this biallelic PKD1 variant, p.Arg3277Cys, leads to rapidly progressive and severe disease with very early-onset ADPKD. Conclusion: Our findings suggest that targeted gene panel sequencing is expected to be the method of choice to improve diagnostic and prognostic accuracy in PKD patients with heterogeneity in genetic background. Keywords: Autosomal dominant, Iranian families, Next generation sequencing, PKD1, PKD2, Polycystic kidney disease, Variants Cite this article as: Hosseinpour M, Ardalani F, Mohseni M, Beheshtian M, Arzhangi S, Ossareh S, et al. Targeted next generation sequencing revealed novel variants in the pkd1 and pkd2 genes of iranian patients with autosomal dominant polycystic kidney disease. Arch Iran Med. 2022;25(9):600-608. doi: 10.34172/aim.2022.95 *Corresponding Author: Kimia Kahrizi, MD; Email: kahrizi@yahoo.com & Behrooz Broumand, MD; Email: v4broumand@yahoo.com 10.34172/aim.2022.95 doi ARCHIVES OF IRANIAN MEDICINE Introduction Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent monogenic kidney disorder with an estimated frequency varying from 1/400 to 1/1000 in the general population. 1 Multiple renal cysts, as the major presentation, invoke enlarged and irregular-shaped kidneys. ADPKD primarily associates with the PKD1 gene [MIM#601313, chromosome 16p13.3] and/or the PKD2 gene [MIM#173910, chromosome 4q21] mutations, 2,3 ascribing 85% and 15% of ADPKD patients, respectively. 4 Stronger association with a severe clinical presentation and poorer prognosis have been reported for mutations in PKD1 than those in the PKD2 gene, suggestive of the critical role of genes in outcome prediction of patients with ADPKD. 4 Due to the allelic heterogeneity, the large size, and complex genomic structure of PKD1 and PKD2, and lack of hotspot site for mutations in these two genes, the genetic analysis of ADPKD is challenging. 5 PKD1 is a complex and large gene that spans 46 exons encoding polycystin-1 with 4303 amino acids. PKD2 contains 15 exons and encodes polycystin-2 consisting of 968 amino acids. Six homologous genes (pseudogenes) on chromosome 16 show 97.7% identity with exons 1 to 33 of PKD1 gene in sequence, carrying larger deletions in comparison to PKD1. 6,7 In patients with mutations in PKD2, a milder clinical course compared to PKD1 patients, fewer renal cysts and milder hypertension (HTN) lead to delayed progression to end-stage kidney failure. 8 A high level of allelic heterogeneity has been observed among ADPKD patients, with over 2300 and 270 germline variants reported to date in PKD1 and PKD2, respectively in Open Access http://www.aimjournal.ir