Abstract: FR-PO970
Biallelic ANKS6 Variants Causing Late Onset Ciliopathy with CKD in Adulthood
Session Information
- PKD Cellular Pathogenesis, ARPKD, ADTKD, Ciliopathies
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidney
- 1002 Genetic Diseases of the Kidney: Non-Cystic
Authors
- Schueler, Markus, University Hospital Erlangen, Erlangen, Germany
- Popp, Bernt, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Knaup, Karl, University of Erlangen-Nuremberg, Erlangen, Germany
- Wiesener, Michael Sean, University Hospital Erlangen, Erlangen, Germany
Background
The progressive and irreversible conditions summarized under the term "Chronic kidney diseases" (CKD) are a heterogeneous group of disorders with significant health and economic effects. Affected individuals and their nephrologists are often unaware of underlying causes. Diagnostic tools used in clinical practice, such as kidney biopsy do not always yield to a definitive diagnosis. High-throughput sequencing methods have advanced our ability to identify the underlying molecular etiology in families with unknown origin of CKD.
Methods
Whole exome sequencing (WES) was performed in two sisters from a non- consanguineous family of German descent who presented with CKD onset in mid-adulthood (>30 years of age). DNA was extracted from whole blood, enriched, and sequenced on a HiSeq2500. In addition patient-derived fibroblasts from skin biopsies were cultured for performing functional studies via immunoblotting.
Results
WES detected two disease associated variants c.[934G>C;938A>C], p.[(A312P);(D313A)]) and c.1973-3C>G in the ANKS6 gene in both affected siblings. Segregation testing by Sanger sequencing confirmed compound heterozygosity. The ciliary protein ANKS6 localizes to the proximal compartment of the cilium, where it regulates ciliary signaling. Mutations in ANKS6 are known to cause Nephronophthisis-related ciliopathies in humans, including laterality defects and congenital hepatic fibrosis. Renal biopsy of both patients showed tubulointerstitial fibrosis and glomerulosclerosis. Careful clinical examination does not reveal any extra-renal findings in both affected individuals. Interestingly, immunoblotting studies from patient-derived fibroblasts show a nearly complete loss of the ANKS6 protein and suggest an effect on gene dosage for both the missense and the splicing variant.
Conclusion
In summary, we confirmed the diagnosis of an ANKS6-associated Nephronophthisis which is typically syndromic and juvenile-onset in two adults with CKD onset in mid-adulthood, highlighting the extreme heterogeneity of CKD. Offering genetic testing to families with renal disease of unknown origin can improve our knowledge of the clinical course in CKD entities, leads to a better understanding of pathophysiological mechanism and may help to develop novel therapeutic strategies, possibly also of relevance to the broader field of kidney diseases.