This report describes a neurodevelopmental disorder postulated to be caused by de novo heterozygous missense variants in the human gene WRDR5. WDR5 encodes a member of the WD repeat protein family, and is involved in several protein regulatory processes. There is one high-scoring fly ortholog, Dmel\wds, for which classical alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. There is also one moderate-scoring ortholog, Dmel\CG10931, which has not been analyzed in a human disease context.
Multiple UAS constructs of the human Hsap\WDR5 gene, including wild-type WDR5 and variants implicated in disease, have been introduced into flies. Variants characterized thus far appear to have occurred de novo; all have been identified as missense variants. See the 'Disease-Implicated Variants' table, below. Heterologous rescue (functional complementation) of Dmel\wds mutants by wild-type Hsap\WDR5 has been demonstrated.
[updated Apr. 2024 by FlyBase; FBrf0222196]
11 unrelated individuals exhibit neurodevelopmental disorders with a spectrum of overlapping additional features, including speech delays (11/11), intellectual disability (9/11), delays in motor development (10/11), hypotonia (6/11), and epilepsy (6/11). (Blok, et al., 2022; pubmed:36285521; FBrf0255186).
Described individuals carry damaging de novo heterozygous variants in WDR5 (Blok, et al., 2022; pubmed:36285521; FBrf0255186).
WDR5 enables methylated histone binding activity. Contributes to histone H3K4 methyltransferase activity. Involved in several processes, including histone modification; regulation of protein modification process; and regulation of transcription by RNA polymerase II. Located in ATAC complex; MLL1/2 complex; and NSL complex. Part of histone acetyltransferase complex and histone methyltransferase complex. [From Alliance of Genome Resources HGNC:12757 automated description; 2022.12.21]
This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. [provided by RefSeq, Jul 2008]
High-scoring ortholog of human WDR5, moderate scoring ortholog of human WDR5b (2 Drosophila to 2 human).
Moderate-scoring ortholog of human WDR5 and WDR5B (2 Drosophila to 2 human).
