Kidney Week

Abstract: FR-PO0142

PLCE1-Associated Nephrotic Syndrome: Burden Analysis and Genotype-Phenotype Correlations in a Large Multicenter Cohort

Session Information

• Hereditary Glomerular and Tubulointerstitial Kidney Diseases
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Zion, Elena, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Elena Zion, MD

• Madariaga, Leire, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Leire Madariaga, MD

• Martinelli, Elena, New York-Presbyterian/Columbia University Irving Medical Center, New York, New York, United States

Elena Martinelli, MD

• Balbach, Maximilian, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Maximilian Balbach

• Ke, Juntao, New York-Presbyterian/Columbia University Irving Medical Center, New York, New York, United States

Juntao Ke, PhD

• Riedhammer, Korbinian M., Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Korbinian M. Riedhammer, MD

• Buerger, Florian, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, United States

Florian Buerger, MD, PhD

• Marchuk, Daniel, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Daniel Marchuk, MD

• Saida, Ken, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Ken Saida, MD, PhD

• Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Martin Pollak, MD

• Sampson, Matt G., Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Matt G. Sampson, MD

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

Rasheed A. Gbadegesin, MD, MBBS, FASN

• Saleem, Moin A., Bristol Renal and Royal Bristol Children Hospital, University of Bristol, Bristol, United Kingdom

Moin A. Saleem, MD, MBBS, MBChB, PhD

• Sanna-Cherchi, Simone, New York-Presbyterian/Columbia University Irving Medical Center, New York, New York, United States

Simone Sanna-Cherchi, MD

• Hildebrandt, Friedhelm, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Friedhelm Hildebrandt, MD

Background

Pathogenic variants in PLCE1 are a rare cause of monogenic nephrotic syndrome (NS). We aimed to examine the frequency and enrichment of biallelic disease-causing PLCE1 variants in a large international NS cohort and to define genotype–phenotype correlations in the largest pediatric PLCE1-associated NS cohort reported to date.

Methods

Exome and genome sequencing data from 5,260 individuals with NS and persistent proteinuria and 28,583 controls were analyzed. We performed a gene-based burden analysis using a collapsing approach under a recessive model, defining qualifying genotypes as those with biallelic likely disease-causing PLCE1 variants. By combining the families identified through this approach with those from our prior studies, we assembled a cohort of 74 individuals (58 families) with PLCE1-associated NS for genotype-phenotype correlation analysis.

Results

We identified 19 individuals with likely disease-causing PLCE1 variants in cases and one in controls. Qualifying genotypes were enriched among NS cases (OR 103.6, CI 19.01–1084, p=2.73×10^-15). All identified individuals in the cases group had steroid-resistant NS with childhood onset (<21 years), accounting for 1% of cases in this subgroup (n=1769). This frequency was comparable to that previously reported in large cohorts. Four novel variants were identified: p.(V326Gfs*22), p.(L1327Rfs*7), p.(L710*) and c.4795+1G>A. Analysis of the expanded PLCE1-associated NS cohort showed that missense variants were clustered (9/10) within the catalytic core, whereas 35 truncating variants were distributed throughout. The median age at onset in the loss-of-function (LoF) variants group was 8 months (IQR 5–18) compared to 24 months (IQR 8–86) in missense variants (p=0.0081). Median age at diagnosis of kidney failure (KF) was 12 months (IQR 8–24) in the LoF variants group and 30 months (IQR 16–120) in the missense group (p=0.043). Time from onset to KF did not differ (p=0.17). Diffuse mesangial sclerosis (DMS) occurred exclusively in individuals with LoF variants (p=0.0016).

Conclusion

The burden analysis approach demonstrated significant enrichment of likely disease-causing PLCE1 genotypes in NS cases compared to controls with a detection rate comparable to the traditional individual-based manual curation. Loss-of-function variants were associated with earlier disease onset and diagnosis of KF, and DMS on kidney biopsy.