Abstract: TH-PO486
Mouse and Human Studies Support DSTYK Loss of Function as a Low Penetrance and Variable Expressivity Risk Factor for Urinary Tract Anomalies and Movement Disorders
Session Information
- Genetic Diseases: Glomerulopathies - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania 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
- Martino, Jeremiah, Columbia University Department of Medicine, New York, New York, United States
- Liu, Qingxue, Columbia University Department of Medicine, New York, New York, United States
- Vukojevic, Katarina, Sveuciliste u Splitu Medicinski fakultet, Split, Croatia
- Ke, Juntao, Columbia University Department of Medicine, New York, New York, United States
- Khan, Atlas, Columbia University Department of Medicine, New York, New York, United States
- Tasic, Velibor, Medical Faculty of Skopje, University Children’s Hospital, Skopje, Macedonia (the former Yugoslav Republic of)
- Ghiggeri, Gian Marco, Division of Nephrology and Renal Transplantation, IRCCS Instituto Giannina Gaslini, Genoa, Italy
- Kiryluk, Krzysztof, Columbia University Department of Medicine, New York, New York, United States
- Mendelsohn, Cathy L., Columbia University Department of Urology, New York, New York, United States
- D'Agati, Vivette D., Columbia University Department of Pathology and Cell Biology, New York, New York, United States
- Gharavi, Ali G., Columbia University Department of Medicine, New York, New York, United States
- Sanna-Cherchi, Simone, Columbia University Department of Medicine, New York, New York, United States
Background
Previous work identified rare variant in DSTYK in humans with congenital anomalies of the kidney and urinary tract (CAKUT). DSTYK coding variants exist at low frequency in the general population, complicating genetic interpretation. Mouse and human studies were used to clarify the association,penetrance and expressivity of DSTYK variants.
Methods
We phenotypically characterized Dstyk knockout mice on 3 genetic backgrounds (C57BL/6J, FVB/NJ and C3H/HeJ). We expanded, characterized and re-sequenced the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to “splice variant” below). DSTYK loss-of-function (LOF) and the splice-site variants were annotated in individuals across different phenotypes: a) CAKUT, b) Epilepsy, and c) amyotrophic lateral sclerosis (ALS) vs. controls. PheWAS analysis was performed using UKBB data.
Results
C57BL/6J Dstyk-/- mice exhibited a 23% penetrance of obstructive uropathy (OU). FVB/NJ Dstyk-/- mice showed a similarly low penetrance, but with added phenotypes of hypoplasia and partial duplication of the kidney and proximal ureter. C3H/HeJ mutants showed a 40% penetrance of OU, but with mild-to-moderate severity. Expansion, re-analysis and re-sequencing of the original family segregating the rare splice-site variant showed low penetrance and no alternative genetic causes for CAKUT. LOF DSTYK variant burden showed significant excess for CAKUT (OR=9.13, P=6.50x10-3), and Epilepsy (OR=6.20, P=1.35x10-2), vs. controls. Enrichment analysis for the splice variant was significant for epilepsy (OR= 6.04, P=1.72x10-2). Literature review and exploratory PheWAS supported association with neurological disorders.
Conclusion
Mouse and human data support causality for DSTYK LoF variants. Large sequencing studies (e.g. >200,000 cases) are required to fully assess the contribution of DSTYK rare variants to lowly-penetrant underlying traits with relatively common population prevalence such as obstructive uropathy. Therefore, while DSTYK LoF variants should not be used to ascertain diagnosis or risk stratification, they may be used in clinical settings when coupled with inheritance information and clinical plausibility.
Funding
- NIDDK Support