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

Jeremiah Martino1, Qingxue Liu1, Katarina Vukojevic2

  • 1Department of Medicine, Columbia University Irving Medical Center, New York, NY.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
|September 25, 2023
PubMed
Abstract

Insights

Rare DSTYK gene variants are linked to congenital kidney and urinary tract anomalies (CAKUT). Our studies confirm DSTYK loss-of-function variants cause CAKUT and neurological disorders, emphasizing large-scale studies for low-penetrance traits.

Area of Science:

  • Genetics
  • Developmental Biology
  • Medical Research

Background:

  • Previous research implicated rare DSTYK variants in congenital anomalies of the kidney and urinary tract (CAKUT).
  • The precise role, penetrance, and expressivity of DSTYK variants in human disease remain incompletely understood.

Purpose of the Study:

  • To clarify the association between DSTYK variants and CAKUT.
  • To investigate the penetrance and expressivity of DSTYK variants in both mouse models and human cohorts.
  • To explore potential links between DSTYK variants and other neurological disorders.

Main Methods:

  • Phenotypic characterization of Dstyk knockout mice across three inbred backgrounds.
  • Re-analysis of a human family with a DSTYK splice-site variant (SSV).
  • Annotation of DSTYK loss-of-function (LOF) and SSVs in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis, and controls.
  • Exploratory phenome-wide association study (PheWAS) using UK Biobank data.

Main Results:

  • Dstyk knockout mice exhibited 20-40% penetrance of obstructive uropathy, varying by genetic background.
  • The studied DSTYK SSV in humans showed low penetrance (43.8%) with no identified alternative genetic causes for CAKUT.
  • A significant excess burden of DSTYK LOF variants was observed in individuals with CAKUT and epilepsy compared to controls.
  • PheWAS results supported an association between DSTYK variants and neurological disorders.

Conclusions:

  • These findings provide strong evidence supporting the causality of DSTYK LOF variants in CAKUT and neurological conditions.
  • The study highlights the critical need for large-scale sequencing initiatives to accurately determine gene and variant causality for low-penetrance, common traits.
Keywords:
Congenital anomalies of the kidney and urinary tractCongenital obstructive uropathyDSTYKDevelopmental kidney diseaseMouse models of kidney disease

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