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| Intellectual disability v2.1055 | DDX6 | Catherine Snow Classified gene: DDX6 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.1055 | DDX6 | Catherine Snow Gene: ddx6 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.1054 | DDX6 | Catherine Snow reviewed gene: DDX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422817; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.1015 | DDX6 |
Konstantinos Varvagiannis gene: DDX6 was added gene: DDX6 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DDX6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DDX6 were set to 31422817 Phenotypes for gene: DDX6 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Unsteady gait; Abnormality of the cardiovascular system; Abnormality of the genitourinary system; Abnormality of limbs Penetrance for gene: DDX6 were set to unknown Review for gene: DDX6 was set to GREEN Added comment: Balak et al. (2019 - PMID: 31422817) report on 5 individuals with de novo likely pathogenic DDX6 variants. Clinical details are provided for 4. Frequent features included hypotonia, DD, ID (4/4), gait instability, cardiac, genitourinary as well anomalies of the extremities. DDX6 belongs to the DEAD box family of RNA helicases. This helicase is an essential component of processing bodies (P-bodies / PBs), which are mebrane-less organelles involved in storage of mRNAs and proteins related to mRNA decay thus playing an important role in translational repression/post-transcriptional regulation (PMID: 29381060). All 5 variants had occurred as de novo events, clustered in exon 11 (NM_004397.5) and affected residues 372-373 of the QxxR motif (c.1115A>G or p.His372Arg / c.1118G>A or p.Arg373Gln) or 390-391 of the V motif (c.1168T>C or p.Cys390Arg / c.1171A>C or p.Thr391Pro / c.1172C>T or p.Thr391Ile). The specific motifs (and RecA-2 domain) are involved in RNA binding, helicase activity and protein-partner binding. Fibroblasts from 2 individuals were studied. Patient cells contained fewer PBs compared to cells from relatives/control-subjects, despite similar amounts of DDX6 protein upon immunobloting. Additional studies suggested that DDX6 variants caused impaired binding of other DDX6 protein partners involved in PB formation / translation repression (eg. LSM14A, 4E-T, etc) thus resulting in defective PB assembly. Transcriptome analysis in fibroblasts from one affected individual revealed (significant) differential expression of >1000 genes, enriched for genes related to protein translation, ribosome and RNA processing. As the authors discuss, given the residual PB assembly, haploinsufficiency is favored over a dominant-negative effect which would result in complete suppression of PBs (as sugested by a previous study of a dominant-negative DDX6 variant - PMID cited: 19297524). [In gnomAD, DDX6 has a Z-score for missense variants of 3.78 and a pLI of 1]. DDX6 is not associated with any phenotype in OMIM. In G2P it is associated with ID (disease confidence : probable / mutations : all missense/in frame). As a result, this gene can be considered for inclusion in the ID panel as green (sufficient cases, relevant phenotype, functional studies) or amber. Sources: Literature |
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