UNRAVELLING THE GENETIC COMPLEXITY OF JUVENILE NEPHRONOPHTHISIS: A NOVEL TTC21B MUTATION AND POTENTIAL FOR ADOLESCENT ONSET

E-Poster

Abstract Title

First Name *

Wesley

Last Name *

van Hougenhouck-Tulleken

Co-author 1

Ali Kiyaei ali@origenes.bio University of Cape Town Department of Molecular and Cell Biology Cape Town

Co-author 2

Patience Sigwadi lusuno@mweb.co.za Netcare Unitas Hospital Paediatric Nephrology Pretoria

Co-author 3

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Introduction

Nephronophthisis (NPHP) is a genetically heterogeneous ciliopathy characterized by cortico-medullary cyst formation and fibrosis leading to end-stage kidney disease, often associated with extra-renal findings. This study explores the genetic basis of NPHP in a South African family affected by its juvenile form.

Methods

Whole Exome Sequencing (WES) was conducted on genomic DNA from a family with three of five children diagnosed with Juvenile Nephronophthisis and requiring dialysis before age three. Quality-controlled Illumina reads were mapped to the hg38 human genome, with variants called and annotated. Identified variants were parsed for known NPHP causative genes and assessed for pathogenicity according to the American College of Medical Genetics and Genomics standards.

Results

WES identified polymorphisms in ANKS6, CEP164, CEP290, NPHP3, NPHP4, TMEM67, TTC21B, and ZNF423 genes. Notably, a novel stop codon was discovered in TTC21B, and a splice site variant in NPHP4 (Figure 1). Minor allele frequencies (MAF) varied, with some polymorphisms having a high minor allele frequency, questioning their pathogenicity. WES on one sibling failed quality control.

Conclusions

The presence of a novel TTC21B stop codon and the polymorphism rs140511594 in affected individuals, along with their low frequency in the general population, supports their pathogenicity in NPHP. Conversely, the absence of the splice site variant rs1287637 in affected individuals suggests its benign nature, which is supported by its relatively high MAF. Interestingly, unaffected siblings carried multiple polymorphisms that could potentially be pathogenic. These siblings may represent cases of late-onset Juvenile or Adolescent NPHP, necessitating ongoing surveillance to determine the actual clinical impact of these variants.

The study highlights a novel pathogenic TTC21B allele in Juvenile Nephronophthisis and the complexity of genetic interpretation. The presence of possible pathogenic alleles in unaffected siblings suggests a broader spectrum of NPHP phenotypes, reflecting the intricate nature of its genetic inheritance and expression.

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