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Abstract: SA-PO525

Assessing the Allelic Spectrum and Pathogenicity of Novel Variants in NPHS2 in 238 Individuals With Steroid-Resistant Nephrotic Syndrome

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Nicolas Frank, Camille H., Boston Children's Hospital, Boston, Massachusetts, United States
  • Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
  • Mertens, Nils David, Boston Children's Hospital, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background

Recessive variants in NPHS2 are the second most frequent cause of steroid-resistant nephrotic syndrome (SRNS) and show a wide spectrum of age of onset. There is no well-established loss-of-function screening assay and clinical databases such as ClinVar are insufficient to determine the deleteriousness of newly detected NPHS2 variants. It was suggested that in silico scores can substitute for the lack of high-throughput functional assays. In addition to homozygous variants, specific compound heterozygosity with the common variant R229Q has been described in Tory, Nat Genet 46:299, 2014. We tested the hypothesis, that R229Q variant is only pathogenic when combined with a compound heterozygote variant encoding for an amino acid in the C-terminal domain (residue 124-383).

Methods

We re-examined an international cohort of 2,300 individuals with SRNS in whom we had performed exome sequencing and multiplex PCR sequencing (Fluidigm) with a specific emphasis on likely-causative, homozygous missense and compound-heterozygous (in combination with R229Q) variants in NPHS2. We generated in silico scores (REVEL, EVE) for homozygous missenses NPHS2 likely causative variants identified in this cohort.

Results

Likely causative NPHS2 variants were identified in 238/2,300 individuals (10%). In 113/238 (47%) individuals, one among 27 different homozygous missense variants was detected. EVE and REVEL scores, calculated for the 27 variants, were plotted to the corresponding individual’s median age of onset. Higher REVEL scores negatively correlated with median age of onset (p<0.03), whereas EVE scores did not (p=0.23). 37 out of 238 individuals (15%) with SRNS had a R229Q variant combined with one of 16 different likely causative variants as the alternative allele (in trans). 8 were previously published, whereas we identified 5 new missense variants, and 3 undescribed C-terminal truncating variants. Interestingly, all 16 mapped onto the C-terminal protein domain.

Conclusion

In NPHS2, we detected a correlation between REVEL deleteriousness score and age of SRNS onset. We confirmed that R229Q is only pathogenic when combined with a variant encoding for an amino acid in the C-terminal domain of podocin (residue 124-383).

Funding

  • NIDDK Support