Whole-Exome Sequencing Application for Genetic Diagnosis of Kidney Diseases: A Study from Southwest of Iran

Abstract

Introduction The kidneys have important and vital functions and provide maintenance of overall body health. Many kidney diseases are caused by single gene defects. Kidney disease is categorized in a heterogeneous group of disorders affecting the kidney, both in structure and function. The end stage of kidney disease is known as kidney failure. Kidney disease is divided into two forms: AKI and CKD (1). Among kidney diseases, polycystic kidney disease (PKD; also known as polycystic kidney syndrome) is revealed to have a genetic background (2). PKD is characterized by the presence of cysts in kidneys. The development and growth of cysts causes abnormalities in the renal tubules. PKD is a clinically and genetically heterogeneous disease (2,3). Clinical characteristics of autosomal dominant and recessive forms of PKD are variable in their penetrance. A range from neonatal death to incidence in old age was reported for PKD (2,4). Disease causing variants in three genes including PKD1, PKD2, and PKDH1 can cause PKD. The pathogenic variations in the PKD1 and PKD2 genes can cause an autosomal dominant (ADPKD) pattern of inheritance. The pathogenic variations in PKDH1 can cause an autosomal recessive (ARPKD) pattern of inheritance (2). There are more than 500 monogenic causes of CKD (5) and numerous genes are listed in next-generation sequencing (NGS) panels for PKD, including ALG9, ANKS6, ATP6V0A4, BICC1, GANAB, GLIS3, HNF1B, INVS, LRP5, MUC1, NOTCH2, NPHP3, OFD1, PKD1, PKD2, PKHD1, SEC61A1, TMEM231, TSC1, TSC2, UMOD, and ZNF423, etc. (2). For classification, preprognosis, monitoring and treatment, and identification of the etiology of the disease is necessary. It helps us understand the scenario of the disorder’s causes and select the best approach for drug treatment (6). NGS is a powerful technique that enables rapid and costeffective parallel sequencing of large panels of genes or whole-exome sequences. However, the targeted panel sequencing approach related to the Whole-Exome Sequencing (WES) is confirmed to provide deep coverage of specific sequences, but WES can provide an opportunity for novel variation detection (7–9). Regarding the polygenic entity of kidney diseases, which means many genes are involved in the pathogenesis of disease, for example, for FSGS, pathogenic variants in more than 20 podocyte-specific genes, such as NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4, and INF2, were announced (10). In fact, conventional Sanger sequencing may be very time consuming and expensive, so using NGS would be helpful. In our study, we identified probable pathogenic variations associated with CKD using WES.