Mouse and human studies support DSTYK loss of function as a low-penetrance and variable expressivity risk factor for congenital urinary tract anomalies

Genet Med. 2023 Dec;25(12):100983. doi: 10.1016/j.gim.2023.100983. Epub 2023 Sep 21.


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.

Keywords: Congenital anomalies of the kidney and urinary tract; Congenital obstructive uropathy; DSTYK; Developmental kidney disease; Mouse models of kidney disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epilepsy* / genetics
  • Humans
  • Kidney / abnormalities
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Penetrance
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Risk Factors
  • Urinary Tract*
  • Urogenital Abnormalities* / genetics


  • DSTYK protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases

Supplementary concepts

  • Cakut