Recent advances in exome/genome sequencing resulted in the identification of numerous novel genes involved in congenital human disorders. However, despite this progress, many families still do not receive a genetic diagnosis. This is particularly difficult for families affected by complex conditions ?without a name? making their disease management and life planning especially challenging. Identification of an underlying genetic cause allows for better categorization of these complex phenotypes, identification of common and variable features, and initiation of studies into disease mechanisms. We recently identified a novel factor, WDR37, as causative in a complex syndromic phenotype including Peters anomaly and coloboma of the eye, short stature, global developmental delay, microcephaly, seizures, and heart defects. The function of this gene is currently unknown with no analyses performed in humans or animal models. In this exploratory proposal, we plan to execute studies to better understand the phenotypic spectrum associated with WDR37 deficiency, develop zebrafish models carrying human-like variants in this gene, and gain the first insights into its embryonic function. Specifically, we plan 1) to define the role of WDR37/wdr37 in vertebrate development and human disease by analyses of human patients and zebrafish lines carrying human-like disease- associated variants and 2) to determine the functional role(s) of WDR37/wdr37 factors by analysis of wild-type and mutant constructs in human cell culture and zebrafish model carrying missense and loss-of-function variants in wdr37. These studies will provide the first data regarding WDR37 function and the spectrum of associated birth defects. In addition to this, our improved understanding of the mechanisms of congenital syndromes will lead to new insights into human embryonic development and is likely to provide new targets for medical intervention and treatment.

Public Health Relevance

This proposal will investigate WDR37, that we found to harbor pathogenic variants in human patients with complex congenital phenotypes. The results of this project will lead to better understanding of embryonic development and likely identify new causes of human congenital conditions, which may result in new diagnostic and treatment opportunities.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD099701-02
Application #
9980441
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Toyama, Reiko
Project Start
2019-07-20
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Pediatrics
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226