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Kidney Week

Abstract: SA-PO399

Incidence of Single Heterozygous Variants in "Nephrotic" Genes in Non-Genetic Paediatric Steroid-Resistant Nephrotic Syndrome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Platt, Caroline Jane, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom
  • Bierzynska, Agnieszka, University of Bristol, Bristol, United Kingdom
  • Koziell, Ania B., Kings College London, London, United Kingdom
  • Welsh, Gavin Iain, University of Bristol, Bristol, United Kingdom
  • Saleem, Moin, University of Bristol, Bristol, United Kingdom

Steroid resistant nephrotic syndrome (SRNS) is a rare condition in childhood associated with considerable morbidity, particularly in those with early onset disease. Up to 30% of children have a monogenic cause, and research is focusing on stratifying patients at an early stage in order to ‘personalise’ their treatments.
Over 70 genes have been associated with SRNS to date, most of them are autosomal recessive (AR). Exome analysis will not infrequently identify single rare heterozygous variants within AR genes that can cause uncertainty. It is often speculated that a second variant was either missed or lies within the non-coding part of the gene. There are pathogenic single heterozygous variants within recessive ‘nephrotic’ genes in the general population (‘carriers’ for the disease).
This pilot project aims to compare the incidence of rare variants in randomly selected AR ‘nephrotic’ genes in paediatric SRNS patients with the ‘general’ population.


133 exome sequenced Caucasian SRNS patients and the ethnically matched ‘general’ population data (gnomAD, exomes) were used for the analysis. Rare (MAF<0.01) single nucleotide variants (SNVs) from the coding and splice-site regions were selected from the AR genes and their incidence was compared between the two cohorts. The data was analysed in 3 consecutive stages: 1. Rare SNVs regardless of zygosity. 2. Rare heterozygous SNVs (not found as homozygotes in any cohort). 3. Rare heterozygous SNVs + small indels, predicted to be likely pathogenic. SRNS patients with confirmed monogenic disease were excluded from this analysis.


In this preliminary work we have found no statistically significant difference in the frequency of rare variants in NS genes (seen as homozygous or heterozygous (48.4% cohort / 53.1% control) / only as heterozygous (27.5% cohort / 24.6% control) / heterozygous and likely pathogenic (7.7% cohort / 8.1% control)) between SRNS patients and the control population.


Our preliminary findings suggest, for the case of the likely pathogenic single heterozygous variants, that these may be incidental and not indicative of a missing ‘second hit’ within the gene.