Kidney Week

Abstract: FR-PO1010

Rare Variants in PLCG2 in a Large Cohort of Multi-ethnic Children With Nephrotic Syndrome

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

• Lane, Brandon M., Duke University School of Medicine, Durham, North Carolina, United States

Brandon M. Lane,

• Varner, Jennifer D., Duke University School of Medicine, Durham, North Carolina, United States

Jennifer D. Varner,

• Chryst-Stangl, Megan, Duke Molecular Physiology Institute, Durham, North Carolina, United States

Megan Chryst-Stangl,

• Wu, Guanghong, Duke University School of Medicine, Durham, North Carolina, United States

Guanghong Wu,

• Hall, Gentzon, Duke University Medical Center, Durham, North Carolina, United States

Gentzon Hall,

• Spurney, Robert F., Duke University Medical Center, Durham, North Carolina, United States

Robert F. Spurney,

• Adeyemo, Adebowale A., National Institutes of Health, Bethesda, Maryland, United States

Adebowale A. Adeyemo,

• Gbadegesin, Rasheed A., Duke University School of Medicine, Durham, North Carolina, United States

Rasheed A. Gbadegesin,

Background

We have previously shown that variants in PLCG2 are associated with the development of SSNS in a cohort of South Asian children. PLCγ2 is an essential signaling component of leukocyte driven adaptive immunity and inflammation. Therefore, we hypothesized that PLCG2 variants are associated with pattern of response to corticosteroid therapy in NS and variability in prevalence of NS across ancestries/ethnicities.

Methods

We performed high throughput next generation targeted sequencing of PLCG2 in a multi-ethnic cohort of 583 children with the nephrotic syndrome. Identified variants that are likely to have effects on gene function (missense, stop codon, frameshift, and obligatory splice site variants) were compared with presumed controls in the gnomAD database. Additionally, we analyzed specific PLCG2 variants and their association with steroid therapy response (SSNS vs SRNS) and ancestry (European, African, Asian) in our cohort.

Results

We identified 10 distinct variants that are associated with NS in our multi ethnic cohort, most of which were associated with SSNS (majority with p<0.001). One of the variants (N174H) is novel, i.e. absent from all public databases. Seven of the variants are predicted to be pathogenic by in silico analysis and one occurs at an obligatory splice site (Q838). The variants associated with SSNS are grouped tightly in the EF-hand domain that is predicted to affect calcium binding and in the autoregulatory region, a region that is linked to increased PLCγ2 activity and inflammation. Variant burden was associated with disease in patients with European or Asian ancestry but not in those of African ancestry.

Conclusion

Rare variants in PLCG2 are associated with NS and may predict the pattern of response to therapy. The clustering of variants in specific PLCγ2 regulatory domains suggests that these variants are important in the pathogenesis of NS and pattern of response to therapy. Furthermore, this data indicates that SSNS-associated variants in PLCG2 may alter calcium-dependent inflammation signaling.

Funding

• NIDDK Support