The Democratization of Genomic Inquiry Empowers Our Understanding of Nephrotic Syndrome

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The early history of inquiry into the genomic underpinnings of nephrotic syndrome (NS) can be roughly characterized as a small number of investigators with technological and analytical expertise, financial resources, and access to large kindreds with congenital or steroid-resistant (SR)NS discovering genes harboring rare coding variants sufficiently damaging to a protein to cause disease. The discovery of “Mendelian NS genes” was paralleled by efforts to assess the phenotypic correlates for those patients diagnosed with “Mendelian” NS. These early genotype-phenotype studies found that patients with Mendelian NS almost always had SRNS but did not have recurrence of NS after kidney transplant (KT).1 However, until recently, the generalizability of these findings to a wider spectrum of genes and patients was unknown.
Fortunately, the rapid advancements in next generation sequencing technologies and their concomitant decrease in cost has led to the democratization of diagnostic screening for Mendelian NS. Investigators worldwide have now sequenced up to 50 Mendelian NS genes in many thousands of patients with NS.2-4 These studies have reinforced that the prevalence of Mendelian NS is higher in children with familial disease, those from countries with higher rates of consanguinity, who had an earlier age of onset, and who are SR (although there is increasing recognition that some patients with Mendelian NS in fact do achieve complete remission of proteinuria5). Also, for patients who progressed to KT, those with a Mendelian form of NS rarely had recurrent disease.3 Altogether, these insights represent major gains toward our efforts provide a precision medicine approach to NS.
Yet, we still have an incomplete understanding of the prevalence of pathogenic genetic variation in known Mendelian NS genes and their associated clinical impact. Part of this knowledge gap can be addressed by sequencing more genes in more patients from previously studied populations. However, perhaps greater gains can be made by expanding the scope of genomic inquiry to populations who have been previously understudied. Thus, the article by Feltan et al,6 reporting the results of their targeted sequencing study in 95 Brazilian children who had undergone a KT for noncongenital forms of NS, is a welcome addition to the NS diagnostic sequencing literature.
The group focused on children diagnosed with NS after 3 months of age referred to 1 of 2 transplant centers in Sao Paolo, Brazil, who underwent KT at an age less than 19 months and who had at least 6 months of follow-up. They screened 139 available children followed by extensive chart review and family interviews. In this way, they excluded 44 patients due mostly to death, graft loss, inability to locate the patients, or a nonnephrotic cause for KT. They then sequenced 24 implicated NS genes, including collagens 4A3, 4, and 5 and apolipoprotein L1 (APOL1), using PCR amplification methods paired with next-generation sequencing. A rigorous bioinformatics pipeline was used, and variants were classified as pathogenic using the standard American College of Medical Genetics guidelines.
They classified 8 (8.4%) of 95 of these transplanted children with Mendelian NS, and 5 (5.2%) of 95 with possible Mendelian NS. Another 8.4% (8/95) of the children were classified with a high-risk APOL1 genotype, another genetic form of their disease (“APOL1-associated NS”). No children with a definite or possible genetic form of their disease had posttransplant recurrence (0/21). Of the remaining 74 children, the recurrence rate was 31% (23/74).
The clinical characteristics of this study are unique and a major strength. For one, it is the first published study to focus exclusively on those children who reached end-stage renal disease (ESRD) from NS.
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