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H3Africa is developing capacity for health-related genomics research in Africa

Steroid-resistant nephrotic syndrome (SRNS) is the most severe form of childhood nephrotic syndrome with an increased risk of progression to chronic kidney disease stage 5. Research endeavors to date have identified more than 80 genes that are associated with SRNS. Most of these genes regulate the structure and function of the podocyte, the visceral epithelial cells of the glomerulus. Although individuals of African ancestry have the highest prevalence of SRNS, especially those from Sub-Saharan Africa (SSA), with rates as high as 30–40% of all cases of nephrotic syndrome, studies focusing on the characterization and understanding of the genetic basis of SRNS in the region are negligible compared with Europe and North America. Therefore, it remains unclear if some of the variants in SRNS genes that are deemed pathogenic for SRNS are truly disease causing, and if the leading causes of monogenic nephrotic syndrome in other populations are the same for children in SSA with SRNS. Other implications of this lack of genetic data for SRNS in the region include the exclusion of children from the region from clinical trials aimed at identifying potential novel therapeutic agents for this severe form of nephrotic syndrome. This review underlines a need for concerted efforts to advance the genetic basis of SRNS in children in SSA. Such endeavors will complement global efforts at understanding the genetic basis of nephrotic syndrome. [ABSTRACT FROM AUTHOR]

The pathogenesis of childhood-onset nephrotic syndrome (NS), disparity in incidence of NS among races, and variable responses to therapies in children with NS have defied explanation to date. In the last 20 years over 50 genetic causes of steroid-resistant nephrotic syndrome (SRNS) have been identified, and at least two disease loci for two pathologic variants of SRNS (focal segmental glomerulosclerosis and membranous nephropathy) have been defined. However, the genetic causes and risk loci for steroid-sensitive nephrotic syndrome (SSNS) remain elusive, partly because SSNS is relatively rare and also because cases of SSNS vary widely in phenotypic expression over time. A recent study of a well-defined modest cohort of children with SSNS identified variants in HLA-DQA1 as a risk factor for SSNS. Here we review what is currently known about the genetics of SSNS and also discuss how recent careful phenotypic and genomic studies reinforce the role of adaptive immunity in the molecular mechanisms of SSNS. [ABSTRACT FROM AUTHOR]

Background: Primary vesicoureteral reflux (PVUR) is the most common malformation of the kidney and urinary tract, and reflux nephropathy is a major cause of chronic kidney disease in children. Recently, we reported mutations in the tenascin XB gene ( TNXB) as a cause of PVUR with joint hypermobility. Methods: To define the role of rare variants in tenascin genes in the etiology of PVUR, we screened a cohort of patients with familial PVUR (FPVUR) and non-familial PVUR (NFPVUR) for rare missense variants in TNXB and the tenascin C gene ( TNC) after excluding mutations in ROBO2 and SOX17. Results: The screening procedure identified 134 individuals from 112 families with PVUR; two families with mutations in ROBO2 were excluded from further analysis. Rare missense variants in TNXB were found in the remaining 110 families, of which 5/55 (9 %) families had FPVUR and 2/55 (4 %) had NFPVUR. There were no differences in high-grade reflux or renal parenchymal scarring between patients with and without TNXB variants. All patients with TNXB rare variants who were tested exhibited joint hypermobility. Overall we were able to identify causes of FPVUR in 7/57 (12 %) families (9 % in TNXB and 3 % in ROBO2). Conclusions: In conclusion, the identification of a rare missense variant in TNXB in combination with a positive family history of VUR and joint hypermobility may represent a non-invasive method to diagnose PVUR and warrants further evaluation in other cohorts. [ABSTRACT FROM AUTHOR]

Background: Mutations in podocin (NPHS2) are the most common cause of childhood onset autosomal recessive steroid-resistant nephrotic syndrome (SRNS). The disease is characterized by early-onset proteinuria, resistance to immunosuppressive therapy and rapid progression to end-stage renal disease. Compound heterozygous changes involving the podocin variant R229Q combined with another pathogenic mutation have been associated with a mild phenotype with disease onset often in adulthood. Methods: We screened 19 families with early-onset SRNS for mutations in NPHS2 and WT1 and identified four disease-causing mutations (three in NPHS2 and one in WT1) prior to planned whole-exome sequencing. Results: We describe two families with three individuals presenting in childhood who are compound heterozygous for R229Q and one other pathogenic NPHS2 mutation, either L327F or A297V. One child presented at age 4 years (A297V plus R229Q) and the other two at age 13 (L327F plus R229Q), one with steadily deteriorating renal function. Conclusions: These cases highlight the phenotypic variability associated with the NPHS2 R229Q variant plus pathogenic mutation. Individuals may present with early aggressive disease. [ABSTRACT FROM AUTHOR]

Advances in kidney genomics in the past 20 years has opened the door for more precise diagnosis of kidney disease and identification of new and specific therapeutic agents. Despite these advances, an imbalance exists between low-resource and affluent regions of the world. Individuals of European ancestry from the United States, United Kingdom, and Iceland account for 16% of the world's population, but represent more than 80% of all genome-wide association studies. South Asia, Southeast Asia, Latin America, and Africa together account for 57% of the world population but less than 5% of genome-wide association studies. Implications of this difference include limitations in new variant discovery, inaccurate interpretation of the effect of genetic variants in non-European populations, and unequal access to genomic testing and novel therapies in resource-poor regions. It also further introduces ethical, legal, and social pitfalls, and ultimately may propagate global health inequities. Ongoing efforts to reduce the imbalance in low-resource regions include funding and capacity building, population-based genome sequencing, population-based genome registries, and genetic research networks. More funding, training, and capacity building for infrastructure and expertise is needed in resource-poor regions. Focusing on this will ensure multiple-fold returns on investments in genomic research and technology. [Display omitted] [ABSTRACT FROM AUTHOR]

Focal and segmental glomerulosclerosis (FSGS) is an important cause of steroid-resistant nephrotic syndrome in adults and children. It is responsible for 5-20% of all cases of end-stage kidney disease (ESKD) in the United States. The pathogenesis of FSGS has not been fully elucidated; however, data from molecular studies of familial cases in the last two decades suggest that FSGS is a defect of the podocyte. The therapeutic agents available for treatment of FSGS are not very effective and only a small percentage of affected individuals will achieve complete remission. Recent data from molecular biology and molecular genetics has provided insight into the mechanisms of action of old agents and also identification of other novel therapeutic targets. This review focuses on recent advances in the molecular pathogenesis of FSGS and currently available therapeutic agents as well as potential novel therapies. [ABSTRACT FROM AUTHOR]

Evolutionary processes, including mutation, migration and natural selection, have influenced the prevalence and distribution of various disorders in humans. However, despite a few well-known examples, such as the APOL1 variants - which have undergone positive genetic selection for their ability to confer resistance to Trypanosoma brucei infection but confer a higher risk of chronic kidney disease - little is known about the effects of evolutionary processes that have shaped genetic variation on kidney disease. An understanding of basic concepts in evolutionary genetics provides an opportunity to consider how findings from ancient and archaic genomes could inform our knowledge of evolution and provide insights into how population migration and genetic admixture have shaped the current distribution and landscape of human kidney-associated diseases. Differences in exposures to infectious agents, environmental toxins, dietary components and climate also have the potential to influence the evolutionary genetics of kidneys. Of note, selective pressure on loci associated with kidney disease is often from non-kidney diseases, and thus it is important to understand how the link between genome-wide selected loci and kidney disease occurs in relation to secondary nephropathies. [ABSTRACT FROM AUTHOR]