Abstract: FR-PO670
Systematic Screening of ADTKD-MUC1 27dupC Variant through Exome Sequencing
Session Information
- Genetic Kidney Diseases: Cohort Studies - Genetic Associations and Diagnoses
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Mesnard, Laurent, Sorbonne Universite, Paris, Île-de-France, France
- Bensouna, Ilias, Sorbonne Universite, Paris, Île-de-France, France
- Robert, Thomas, Assistance Publique Hopitaux de Marseille, Marseille, France
- Raymond, Laure, Eurofins Biomnis Lyon, Lyon, France
- Serveaux Dancer, Marine, Eurofins Biomnis Lyon, Lyon, France
Background
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is associated with pathological variants in the MUC1 gene. Traditional next-generation sequencing (NGS) methods struggle with the variable number tandem repeat (VNTR) region in MUC1, where the pathogenic “27DupC” variant is found in over 80% of cases. We propose a novel pipeline using a k-mer approach to detect variants in this challenging region, optimized for exome sequencing, which typically cannot identify these variations due to the VNTR.
Methods
wo tools were employed: Shark®, which targets the MUC1 region and reduces data processing time, and VNtyper®, which uses the k-mer approach for variant calling. The SharkVNTyper pipeline was first evaluated in 26 positive and 52 negative control samples. Next, retrospective analysis was conducted on 3512 patients with chronic kidney disease (CKD) and exome sequencing, and prospective analysis started in November 2023 on 825 patients. Snapshot PCR, specifically targeting 27dupC, was used to confirm positive SharkVNTyper results.
Results
SharkVNTyper identified the 27dupC variant in 25 out of 26 positive controls (96.2%) and found no variants in the 52 negative controls. Among the 4337 patients in the combined retrospective and prospective cohorts, SharkVNTyper detected a frameshift variant in 36 patients previously lacking a molecular diagnosis. Snapshot PCR confirmed the presence of 27dupC in 30 of these cases, leading to unexpected diagnoses of ADTKD-MUC1 for these patients. Patients with typical ADTKD with non-27DupC variants are under scrutiny for similar bioinformatic development.
Conclusion
Utilizing bioinformatics tools based on the k-mer method allows for effective analysis of the MUC1 VNTR. This approach facilitates the diagnosis of ADTKD-MUC1 from exome sequencing data in CKD patients, specifically identifying the critical 27dupC variant for systematic screening from the exome output.
Chart 1: Proposed diagnostic framework for 27dupC detection responsible for ADTKD-MUC1 with ES