Next-Generation Sequencing-Based Genetic Diagnostic Strategies of Inherited Kidney Diseases

Abstract

<b><i>Background:</i></b> At least 10% of adults and most of the children who receive renal replacement therapy have inherited kidney diseases. These disorders substantially decrease their life quality and have a large effect on the health-care system. Multisystem complications, with typical challenges for rare disorders, including variable phenotypes and fragmented clinical and biological data, make genetic diagnosis of inherited kidney disorders difficult. In current clinical practice, genetic diagnosis is important for clinical management, estimating disease development, and applying personal treatment for patients. <b><i>Summary:</i></b> Inherited kidney diseases comprise hundreds of different disorders. Here, we have summarized various monogenic kidney disorders. These disorders are caused by mutations in genes coding for a wide range of proteins including receptors, channels/transporters, enzymes, transcription factors, and structural components that might also have a role in extrarenal organs (bone, eyes, brain, skin, ear, etc.). With the development of next-generation sequencing technologies, genetic testing and analysis become more accessible, promoting our understanding of the pathophysiologic mechanisms of inherited kidney diseases. However, challenges exist in interpreting the significance of genetic variants and translating them to guide clinical managements. Alport syndrome is chosen as an example to introduce the practical application of genetic testing and diagnosis on inherited kidney diseases, considering its clinical features, genetic backgrounds, and genetic testing for making a genetic diagnosis. <b><i>Key Messages:</i></b> Recent advances in genomics have highlighted the complexity of Mendelian disorders, which is due to allelic heterogeneity (distinct mutations in the same gene produce distinct phenotypes), locus heterogeneity (mutations in distinct genes result in similar phenotypes), reduced penetrance, variable expressivity, modifier genes, and/or environmental factors. Implementation of precision medicine in clinical nephrology can improve the clinical diagnostic rate and treatment efficiency of kidney diseases, which requires a good understanding of genetics for nephrologists.

Diagnostic application of exome sequencing in Chinese children with suspected inherited kidney diseases

“…Inherited kidney diseases (IKDs) are a group of kidney diseases characterized by abnormal kidney structure or function caused by genetic factors which present substantial clinical heterogeneity in clinical presentation, age of onset, severity, and progression of symptoms, accounting for at least 10%-15% of cases of kidney replacement therapy (Zhang et al, 2021;Torra et al, 2021). So far, there have been more than 150 known IKDs which can be divided into two categories of inherited renal structural abnormality and inherited renal dysfunction (Devuyst et al, 2014;Cunha et al, 2020).…”

Clinical Characteristics, Renal Involvement, and Therapeutic Options of Pediatric Patients With Fabry Disease

“…GLA gene mutation will lead to the deficiency of the alpha-galactosidase A (α-Gal A) enzyme. The most frequent GLA mutations are missense followed by nonsense mutations, but also deletions, duplication, insertions, frameshift, and splice-site mutations are observed ( 11 , 21 ).…”

ADrosophilamodel to screen Alport syndromeCOL4A5variants for their functional pathogenicity

“…The many variants in COL4A5 and their varying pathogenic effect, put to question whether variant location in the type IV Collagen protein contributes to pathogenicity (Daga et al, 2022; Savige et al, 2021; Zhang et al, 2021). Using Drosophila , we tested variants that were either in the triple helix or in the NC1 (a.k.a., C4) domain, at which the three chains of the collagen fiber interact.…”

“…Over time, the GBM deteriorates, resulting in the characteristic GBM splitting and lamellation observed in Alport patient kidney biopsies (Barsotti et al, 2001; Kalluri et al, 1997; Longo et al, 2006; Noël, 2000). To date, nearly 2,000 variants in the COL4A(3,4,5) genes have been linked to Alport syndrome: Most mutations are in the X-linked COL4A5 gene (Daga et al, 2022; Savige et al, 2021), mutations in COL4A3 and COL4A4 on chromosome 2 are often autosomal recessive (Daga et al, 2022); in addition, oligogenicity has been reported (Daga et al, 2022; Savige et al, 2021; Zhang et al, 2021).…”