1. Mouse and human studies support DSTYK loss of function as a low-penetrance and variable expressivity risk factor for congenital urinary tract anomalies.
- Author
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Martino J, Liu Q, Vukojevic K, Ke J, Lim TY, Khan A, Gupta Y, Perez A, Yan Z, Milo Rasouly H, Vena N, Lippa N, Giordano JL, Saraga M, Saraga-Babic M, Westland R, Bodria M, Piaggio G, Bendapudi PK, Iglesias AD, Wapner RJ, Tasic V, Wang F, Ionita-Laza I, Ghiggeri GM, Kiryluk K, Sampogna RV, Mendelsohn CL, D'Agati VD, Gharavi AG, and Sanna-Cherchi S
- Subjects
- Animals, Mice, Humans, Penetrance, Mice, Inbred C3H, Mice, Inbred C57BL, Kidney abnormalities, Risk Factors, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Urinary Tract, Urogenital Abnormalities genetics, Epilepsy genetics
- Abstract
Purpose: Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYK variants., Methods: We phenotypically characterized Dstyk knockout mice of 3 separate inbred backgrounds and re-analyzed the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to as "SSV" below). DSTYK loss of function (LOF) and SSVs were annotated in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis vs controls. A phenome-wide association study analysis was also performed using United Kingdom Biobank (UKBB) data., Results: Results demonstrate ∼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk
-/- mice. Phenotypic penetrance increased to ∼40% in C3H/HeJ mutants, with mild-to-moderate severity. Re-analysis of the original family segregating the rare SSV showed low penetrance (43.8%) and no alternative genetic causes for CAKUT. LOF DSTYK variants burden showed significant excess for CAKUT and epilepsy vs controls and an exploratory phenome-wide association study supported association with neurological disorders., Conclusion: These data support causality for DSTYK LOF variants and highlights the need for large-scale sequencing studies (here >200,000 cases) to accurately assess causality for genes and variants to lowly penetrant traits with common population prevalence., Competing Interests: Conflict of Interest All authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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