title: High throughput in vivo functional validation of candidate congenital heart disease genes inDrosophila.
abstract: Genomic sequencing has implicated large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system is needed to validate gene associations with pathology. We developed aDrosophila-based functional system to screen candidate disease genes identified from Congenital Heart Disease (CHD) patients. 134 genes were tested in theDrosophilaheart using RNAi-based gene silencing. Quantitative analyses of multiple cardiac phenotypes demonstrated essential structural, functional, and developmental roles for more than 70 genes, including a subgroup encoding histone H3K4 modifying proteins. We also demonstrated the use ofDrosophilato evaluate cardiac phenotypes resulting from specific, patient-derived alleles of candidate disease genes. We describe the first high throughput in vivo validation system to screen candidate disease genes identified from patients. This approach has the potential to facilitate development of precision medicine approaches for CHD and other diseases associated with genetic factors.
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States.
authors.forename: Jun-Yi
authors.initials: JY
authors.lastname: Zhu
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: Nettleton
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Richman
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States.
authors.forename: Zhe
authors.identifier: http://orcid.org/0000-0002-5177-7798
authors.initials: Z
authors.lastname: Han
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics*; D020868:Gene Silencing; D005820:Genetic Testing; D006331:Heart Diseases / Q000151:congenital* / Q000235:genetics*; D057166:High-Throughput Screening Assays; D006801:Humans; D034622:RNA Interference
chemical_list: D029721:Drosophila Proteins
keywords: D. melanogaster; Drosophila; congenital heart disease; developmental biology; heart development; histone modification; human biology; in vivo validation; medicine; stem cells