| Title: | Mouse and human studies support DSTYK loss of function as a low-penetrance and variable expressivity risk factor for congenital urinary tract anomalies |
| Journal: | Genetics in Medicine |
| Published: | 21 Sep 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37746849/ |
| DOI: | https://doi.org/10.1016/j.gim.2023.100983 |
Publication 9502
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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.</p>
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.</p>
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.</p>
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.</p>
31 Authors
- Jeremiah Martino
- Qingxue Liu
- Katarina Vukojevic
- Juntao Ke
- Tze Y Lim
- Atlas Khan
- Yask Gupta
- Alejandra Perez
- Zonghai Yan
- Hila Milo Rasouly
- Natalie Vena
- Natalie Lippa
- Jessica L Giordano
- Marijan Saraga
- Mirna Saraga-Babic
- Rik Westland
- Monica Bodria
- Giorgio Piaggio
- Pavan K Bendapudi
- Alejandro D Iglesias
- Ronald J Wapner
- Velibor Tasic
- Fan Wang
- Iuliana Ionita-Laza
- Gian Marco Ghiggeri
- Krzysztof Kiryluk
- Rosemary V Sampogna
- Cathy L Mendelsohn
- Vivette D D'Agati
- Ali G Gharavi
- Simone Sanna-Cherchi
Enabling scientific discoveries that improve human health