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

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An Erratum to this article was published on 27 March 2017

Abstract

Background

More than 30 genes can harbor rare exonic variants sufficient to cause nephrotic syndrome (NS), and the number of genes implicated in monogenic NS continues to grow. However, outside the first year of life, the majority of affected patients, particularly in ancestrally mixed populations, do not have a known monogenic form of NS. Even in those children classified with a monogenic form of NS, there is phenotypic heterogeneity. Thus, we have only discovered a fraction of the heritability of NS—the underlying genetic factors contributing to phenotypic variation. Part of the “missing heritability” for NS has been posited to be explained by patients harboring coding variants across one or more previously implicated NS genes, insufficient to cause NS in a classical Mendelian manner, but that nonetheless have a sufficient impact on protein function to cause disease. However, systematic evaluation in patients with NS for rare or low-frequency risk alleles within single genes, or in combination across genes (“oligogenicity”), has not been reported. To determine whether, compared with a reference population, patients with NS have either a significantly increased burden of protein-altering variants (“risk-alleles”), or a unique combination of them (“oligogenicity”), in a set of 21 genes implicated in Mendelian forms of NS.

Methods

In 303 patients with NS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE), we performed targeted amplification paired with next-generation sequencing of 21 genes implicated in monogenic NS. We created a high-quality variant call set and compared it with a variant call set of the same genes in a reference population composed of 2,535 individuals from phase 3 of the 1000 Genomes Project. We created both a “stringent” and a “relaxed” pathogenicity-filtering pipeline, applied them to both cohorts, and computed the burden of variants in the entire gene set per cohort, the burden of variants in the entire gene set per individual, the burden of variants within a single gene per cohort, and unique combinations of variants across two or more genes per cohort.

Results

With few exceptions when using the relaxed filter, and which are likely the result of confounding by population stratification, NS patients did not have a significantly increased burden of variants in Mendelian NS genes in comparison to a reference cohort, nor was there any evidence for oligogenicity. This was true when using both the relaxed and the stringent variant pathogenicity filter.

Conclusion

In our study, there were no significant differences in the burden or particular combinations of low-frequency or rare protein-altering variants in a previously implicated Mendelian NS genes cohort between North American patients with NS and a reference population. Studies in larger independent cohorts or meta-analyses are needed to assess the generalizability of our discoveries and also address whether there is in fact small but significant enrichment of risk alleles or oligogenicity in NS cases that was undetectable with this current sample size. It is still possible that rare protein-altering variants in these genes, insufficient to cause Mendelian disease, still contribute to NS as risk alleles and/or via oligogenicity. However, we suggest that more accurate bioinformatic analyses and the incorporation of functional assays would be necessary to identify bona fide instances of this form of genetic architecture as a contributor to the heritability of NS.

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    Authors and Affiliations

    1. Department of Pediatrics, University of Michigan Medical School, 3560B MSRB 2, Ann Arbor, MI, USA

      Brendan D. Crawford, Christopher E. Gillies, Catherine C. Robertson, Virginia Vega-Wagner & Matthew G. Sampson

    2. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

      Matthias Kretzler & Edgar Otto

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    1. Brendan D. Crawford
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    2. Christopher E. Gillies
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    Correspondence to Matthew G. Sampson.

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    Funding

    The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research (ORDR), NCATS, and the National Institute of Diabetes, Digestive, and Kidney Diseases. Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, the NephCure Kidney International, and the Halpin Foundation.

    Disclosures

    Brendan Crawford is supported by the National Institutes of Health Kidney Research Training Grant T32DK007378. Matthew Sampson is supported by the Charles Woodson Clinical Research Fund, RO1DK108805, and is a Carl W. Gottschalk Research Scholar of ASN Foundation for Kidney Research.

    Additional information

    Brendan D. Crawford and Christopher E. Gillies contributed equally to this work

    An erratum to this article is available at http://dx.doi.org/10.1007/s00467-017-3653-0.

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    Crawford, B.D., Gillies, C.E., Robertson, C.C. et al. Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability. Pediatr Nephrol 32, 467–476 (2017). https://doi.org/10.1007/s00467-016-3513-3

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