Congenital heart defect (CHD), also described as congenital heart disease, is the most common type of birth defect; it is thought to have a significant genetic component. Candidate genes identified in a large-scale exome sequencing analysis have been assessed in a fly system using cardiac-targeted gene silencing of orthologous fly genes. Based on experiments using the Drosophila ortholog wds, WDR5 has emerged as a high-confidence candidate. WDR5, WD Repeat Domain 5, encodes a protein that is a member of several chromatin modifying complexes. For the fly gene, Dmel\wds, classical loss-of-function mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human Hsap\WDR5 gene, including wild-type and a variant implicated in CHD, have been introduced into flies. Functional complementation (heterologous rescue) has been demonstrated; co-expression of the wild-type Hsap\WDR5 results in dramatic reduction of the larval phenotypes produced by targeted knockdown of Dmel\wds in the developing heart. The tested disease-implicated form exhibits an intermediate phenotype. Variant(s) implicated in human disease tested (as transgenic human gene, WDR5): the K7Q variant form of the human gene has been introduced into flies.
Animals homozygous for loss-of-function mutations of Dmel\wds typically die during the larval stage. Targeted knockdown of wds restricted to the developing heart, effected by RNAi, results in 100% lethality prior to the adult stage. Abnormal heart morphology is observed in late larvae, characterized by reduced cardiac myofibers and over-deposition of the extracellular matrix protein pericardin. Physical and genetic interactions have been described for Dmel\wds; see below and in the wds gene report.
[updated Nov. 2018 by FlyBase; FBrf0222196]
A congenital heart defect is a problem with the structure of the heart; it is the most common type of birth defect. The defects can involve the walls of the heart, the valves of the heart, and the arteries and veins near the heart. They can disrupt the normal flow of blood through the heart: the blood flow can slow down, go in the wrong direction or to the wrong place, or be blocked completely (https://medlineplus.gov/congenitalheartdefects.html).
Defects range from simple, which might cause no problems, to complex, which can cause life-threatening complications. The most serious defects are categorized as critical congenital heart defects (CCHD). CCHD is life threatening and requires intervention in infancy; approximately 18 out of 10,000 babies are born with CCHD (https://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/PEHDIC/Pages/Newborn-Screening-for-CCHD.aspx).
Genetic causes of congenital heart disease also account for many of the comorbidities seen with increased frequency in congenital heart disease patients, including neurodevelopmental disability, pulmonary disease, arrhythmia, renal disease, heart failure and an increased incidence of malignancy. (Simmons and Brueckner, 2017; pubmed:28872494).
A number of well studied syndromes, including DiGeorge syndrome, Williams-Beuren syndrome, Alagille syndrome, Noonan syndrome, and Holt-Oram syndrome, include congenital heart defect (Pierpont et al., 2007; pubmed:17519398).
Congenital heart defects (CHTD) are among the most common congenital defects, occurring with an incidence of 8/1,000 live births. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. [from MIM:306955; 2018.11.13]
WDR5 encodes a member of the WD repeat protein family that contributes to histone modification as a member of the MLL complex (H3-K4 specific histone methyltransferase activity) and of the NSL complex (H4-K8 specific histone acetyltransferase activity). [Gene Cards, WDR5; 2018.11.13]
The fly TRX complex (FBgg0000285) is analogous to the human MLL1/2 complex.
Many to many: 2 human to 2 Drosophila; the human genes are WDR5 and WDR5B.
