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J Am Soc Nephrol. 2019 Sep;30(9):1625-1640. doi: 10.1681/ASN.2019020152. Epub 2019 Jul 15.

Contributions of Rare Gene Variants to Familial and Sporadic FSGS.

Author information

1
Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
2
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
3
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
4
Division of Nephrology, Department of Medicine, University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada.
5
Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
6
Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York.
7
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York; and.
8
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
9
Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; mpollak@bidmc.harvard.edu.

Abstract

BACKGROUND:

Over the past two decades, the importance of genetic factors in the development of FSGS has become increasingly clear. However, despite many known monogenic causes of FSGS, single gene defects explain only 30% of cases.

METHODS:

To investigate mutations underlying FSGS, we sequenced 662 whole exomes from individuals with sporadic or familial FSGS. After quality control, we analyzed the exome data from 363 unrelated family units with sporadic or familial FSGS and compared this to data from 363 ancestry-matched controls. We used rare variant burden tests to evaluate known disease-associated genes and potential new genes.

RESULTS:

We validated several FSGS-associated genes that show a marked enrichment of deleterious rare variants among the cases. However, for some genes previously reported as FSGS related, we identified rare variants at similar or higher frequencies in controls. After excluding such genes, 122 of 363 cases (33.6%) had rare variants in known disease-associated genes, but 30 of 363 controls (8.3%) also harbored rare variants that would be classified as "causal" if detected in cases; applying American College of Medical Genetics filtering guidelines (to reduce the rate of false-positive claims that a variant is disease related) yielded rates of 24.2% in cases and 5.5% in controls. Highly ranked new genes include SCAF1, SETD2, and LY9. Network analysis showed that top-ranked new genes were located closer than a random set of genes to known FSGS genes.

CONCLUSIONS:

Although our analysis validated many known FSGS-causing genes, we detected a nontrivial number of purported "disease-causing" variants in controls, implying that filtering is inadequate to allow clinical diagnosis and decision making. Genetic diagnosis in patients with FSGS is complicated by the nontrivial rate of variants in known FSGS genes among people without kidney disease.

KEYWORDS:

focal segmental glomerulosclerosis; human genetics; kidney

PMID:
31308072
PMCID:
PMC6727251
[Available on 2020-09-01]
DOI:
10.1681/ASN.2019020152

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