The genetic landscape of autosomal dominant polycystic kidney disease in Kuwait

Abstract

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal monogenic disease and characterized by bilateral accumulation of renal fluid-filled cysts leading to progressive renal volume enlargement and gradual impairment of kidney function which often resulting in ESRD. Kuwait could provide valuable genetic insight about ADPKD including intrafamilial phenotypic variation, given its large household size. This study aims to provide a comprehensive description of the pathogenic variants linked to ADPKD in the Kuwaiti population using multiple genetic analysis modalities and to describe and analyze the ADPKD phenotypic spectrum in term of kidney function, kidney volume and renal survival. Methods 126 ADPKD patients from 11 multiplex families and 25 singletons were recruited in the study. A combination of targeted next generation sequencing (tNGS), long range (LR) -PCR, Sanger sequencing and multiplex-ligation dependent probe amplification (MLPA) were utilized for genetic diagnosis. Clinical evaluation was conducted through Renal Function Test (RFT) and ultrasonographic kidney volume analysis. Results We identified 29 ADPKD pathogenic mutations from 36 families achieving an overall molecular genetic diagnostic rate of 112/126 (88.9%) including 29/36 (80.6%) in families. 28/36 (77.8%) of families had pathogenic mutations in PKD1, of which 17/28 (60.7%) were truncating, and 1/36 (2.8%) had a pathogenic variant in IFT140 gene. 20/29 (69%) of the identified ADPKD mutations were novel and described for the first time including a TSC2-PKD1 contiguous syndrome. Clinical analysis indicated that genetically unresolved ADPKD cases had no apparent association between kidney volume and age. Conclusion We describe for the first time the genetic landscape of ADPKD in Kuwait. The observed genetic heterogeneity underlining ADPKD along with the wide phenotypic spectrum reveals the level of complexity in disease pathophysiology. ADPKD genetic testing could improve care of patients through improving disease prognostication, guided treatment, as well as genetic counseling. However, to fulfill the potential of genetic testing, it is important to overcome the hurdle of genetically unresolved ADPKD cases.

Global analysis of urinary extracellular vesicle small RNAs in autosomal dominant polycystic kidney disease

“…Inclusion criteria involved having a confirmed clinical diagnosis of ADPKD with positive genetic test. All patients had PKD1 mutations that were reported previously 6,23,24 . In addition, 28 healthy individuals were included in the study without any record of chronic health condition.…”

“…All patients had PKD1 mutations that were reported previously. 6,23,24 In addition, 28 Prior to participation, written informed consent was obtained from all enrolled patients in accordance with the guidelines set forth by the MOH research committee.…”

“…5 The majority of ADPKD cases (78%) are attributed to mutations in PKD1, whereas around 15% of the cases are caused by mutations in PKD2 gene. 6 Recently, IFT140 has been suggested as the third most common gene linked to ADPKD cases, 7 whereas other rarer forms of the disease have been linked to mutations in genes, including GANAB, DNAJB11 and ALG9. [8][9][10] This genetic heterogeneity has contributed to a wide phenotypic spectrum representing a challenge for disease diagnosis and prognosis, management of patients, genetic counseling, and patients' selection for clinical trials.…”

“…Besides the kidney‐related symptoms, individuals with ADPKD might experience extrarenal manifestations including polycystic liver disease (PLD), cerebral aneurysms, and cardiovascular abnormalities, including early‐onset hypertension 5 . The majority of ADPKD cases (78%) are attributed to mutations in PKD1 , whereas around 15% of the cases are caused by mutations in PKD2 gene 6 . Recently, IFT140 has been suggested as the third most common gene linked to ADPKD cases, 7 whereas other rarer forms of the disease have been linked to mutations in genes, including GANAB , DNAJB11 and ALG9 8–10 .…”

Matching Variants for functional characterization of genetic variants

“…Furthermore, IFT140 is found to regulate the ciliary entry of G protein-coupled receptors (GPCRs) (Absalon et al, 2008; Mukhopadhyay et al, 2010). IFT140 was implicated in several ciliopathies, including Short-Rib Thoracic Dysplasia 9 with or Without Polydactyly (SRTD9: 266920), [also known as Mainzer-Saldino syndrome (MSS), conorenal syndrome and Jeune asphyxiating thoracic dystrophy (JATD)], nonsyndromic retinitis pigmentosa, syndromic congenital retinal dystrophy, and autosomal dominant polycystic kidney disease (ADPKD) (Ali et al, 2023; Bayat et al, 2017; Bifari et al, 2016; Helm et al, 2017; Schmidts et al, 2013; Xu et al, 2015). However, the majority of variants (80%) in human IFT140 submitted to ClinVar are categorized as VUS (Landrum et al, 2018).…”