Abstract: PO1349
Broad Genetic Analysis Reveals Diverse Molecular Causes of Autosomal Dominant Tubulointerstitial Kidney Disease-Not Otherwise Specified (ADTKD-NOS)
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Wopperer, Florian, Universitatsklinikum Erlangen Medizinische Klinik 4 Nephrologie und Hypertensiologie, Erlangen, Bayern, Germany
- Pasutto, Francesca, Universitatsklinikum Erlangen Institut fur Humangenetik, Erlangen, Bayern, Germany
- Wiesener, Michael Sean, Universitatsklinikum Erlangen Medizinische Klinik 4 Nephrologie und Hypertensiologie, Erlangen, Bayern, Germany
Background
A particularly difficult group of diseases to diagnose are the Autosomal Dominant Tubulointerstitial Kidney Diseases (ADTKD). ADTKD is caused by mutations in one of at least five genes and leads to end-stage renal disease usually in mid adulthood. Families where no mutation can be found are therefore termed ADTKD-NOS (not otherwise specified), who are the focus of this study. Herein we investigated 45 families of our ADTKD-registry.
Methods
The study was approved by the institutional ethics committee (protocol number 251_18B). Detailed pedigree analysis and clinical characterisation of kidney diseases were performed, as well as evaluation of historical kidney biopsies, wherever available. Panel sequencing for all known ADTKD candidate genes was performed, followed by SNaPshot minisequencing for the dupC mutation of MUC1. Exome-Sequencing was performed on the HiSeq System 2500 (Illumina) after enrichment by TWIST human core technology (TWIST Bioscience). Initially, 560 genes associated with abnormal renal physiology (Human Phenotype Ontology, https://mseqdr.org/hpo_browser.php?12622, retrieved March 2020) were screened (here termed nephrome). If no disease-causing variants were detected, exome-wide analysis was performed.
Results
In 30 of the 45 registry families mutations in known ADTKD genes were found, most frequently MUC1. In the remaining 15 families diagnostic gene variants were either detected in the nephrome (4x COL4A5, 1x COL4A4x, 2x INF2, 1x PAX2) or the exome, where analysis yielded potentially disease associated variants in novel candidate genes for ADTKD. A list of these candidate genes in the respective families will be presented. All variants segregated within families.
Conclusion
In the great majority of our ADTKD registry families we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases, which should in retrospect be seen as glomerular origin. Atypical clinical presentation, (seemingly) autosomal dominant pedigrees (i.e. COL4-associated disease) and sometimes decades since onset of disease and genetic evaluation have handicapped the classification towards ADTKD-NOS. The other families investigated by exome analysis have partly led to identification of promising novel candidate genes. However, functional studies will need to follow to determine if these variants are truly pathogenic.
Funding
- Government Support – Non-U.S.