Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort

Abstract

To maximize clinical benefits of genetic screening of patients with nephrotic syndrome (NS) to diagnose monogenic causes, reliably distinguishing NS-causing variants from the background of rare, noncausal variants prevalent in all genomes is vital. To determine the prevalence of monogenic NS in a North American case cohort while accounting for background prevalence of genetic variation, we sequenced 21 implicated monogenic NS genes in 312 participants from the Nephrotic Syndrome Study Network and 61 putative controls from the 1000 Genomes Project (1000G). These analyses were extended to available sequence data from approximately 2500 subjects from the 1000G. A typical pathogenicity filter identified causal variants for NS in 4.2% of patients and 5.8% of subjects from the 1000G. We devised a more stringent pathogenicity filtering strategy, reducing background prevalence of causal variants to 1.5%. When applying this stringent filter to patients, prevalence of monogenic NS was 2.9%; of these patients, 67% were pediatric, and 44% had FSGS on biopsy. The rate of complete remission did not associate with monogenic classification. Thus, we identified factors contributing to inaccurate monogenic classification of NS and developed a more accurate variant filtering strategy. The prevalence and clinical correlates of monogenic NS in this sporadically affected cohort differ substantially from those reported for patients referred for genetic analysis. Particularly in unselected, population-based cases, considering putative causal variants in known NS genes from a probabilistic rather than a deterministic perspective may be more precise. We also introduce GeneVetter, a web tool for monogenic assessment of rare disease.

Elevated urinary CRELD2 is associated with endoplasmic reticulum stress–mediated kidney disease

“…Mutations in more than 30 podocyte genes including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4, INF2, and COL4A have been implicated as causal factors for primary podocytopathy and GBM nephropathy (34). With the recent advent of next-generation sequencing, a large number of rare (minor allele frequency < 0.5%) missense variants of unknown significance in both known and novel NS-causing podocyte genes are rapidly emerging in thousands of affected patients (35,36). Due to lack of recurrence and family data for segregation analysis in sporadic patients and patients with de novo mutations, and a sole reliance on bioinformatics-based prediction algorithms, reliably assigning pathogenicity to these genetic variants is challenging (37).…”

Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability

“…Participants were recruited without selection for positive family history of NS, age of onset, or response to therapy. 312 participants with available DNA for sequencing were previously sequenced across these 21 genes to determine the prevalence of monogenic NS in this cohort [14]. We excluded the nine individuals already classified with monogenic NS, resulting in 303 participants included in this study (Table 1).…”

“…For example, we recently performed targeted sequencing of 21 known NS genes in a North American population-based cohort of biopsied NS patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). Using stringent filtering criteria, we classified only 3% of patients with a monogenic cause of their NS [14]. When restricting this analysis solely to children with FSGS or MCD, this prevalence was 5.5%.…”

“…To address this question, we analyzed sequence data from 21 implicated Mendelian NS genes in 303 patients with NS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort (who were previously determined to not have monogenic NS due to variants in these genes) [14] and ~2500 subjects from Phase 3 of the 1000 Genome project (1000G) [24]. We then tested the hypothesis that, as compared to the reference population, patients with NS were enriched for oligogenicity and/or risk alleles within this geneset.…”

The expanding phenotypic spectra of kidney diseases: insights from genetic studies

“…Basal exon skipping is a mechanism by which severely mutated exons can be selectively spliced out of the gene transcript. The resulting shortened transcript escapes nonsense-mediated decay and can retain partial function if the skipped exon was outside an important functional domain (5). Variants in multiple genes can influence the type and severity of phenotypic features.…”