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Intellectual disability

Gene: DDX6

Green List (high evidence)
DDX6 (DEAD-box helicase 6)
EnsemblGeneIds (GRCh38): ENSG00000110367
EnsemblGeneIds (GRCh37): ENSG00000110367
OMIM: 600326, Gene2Phenotype
DDX6 is in 3 panels

2 reviews

Catherine Snow (Genomics England)

Green List (high evidence)

DDX6 identified by Konstantinos Varvagiannis who reviewed PMID: 31422817. 5 unrelated individuals identified all with variants in DDX6, 4/5 has undergone trio WES and were identified using GeneMatcher. All variants identified in the same exon. Another helicase family member, DDX59, identified as involvement in ID, which is rated Green on this panel.
DDX6 is associated with ID and DD phenotype in Gene2Phenotype.
As sufficient unrelated cases with consistent phenotype of DD and ID classifying DDX6 as Green.
Created: 3 Oct 2019, 1:31 p.m. | Last Modified: 3 Oct 2019, 1:31 p.m.
Panel Version: 2.1054

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

Created: 3 Oct 2019, 1:31 p.m.
Last Modified: 3 Oct 2019, 1:31 p.m.
Panel version: 2.1054

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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
Created: 25 Aug 2019, 7:45 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Generalized hypotonia; Global developmental delay; Intellectual disability; Unsteady gait; Abnormality of the cardiovascular system; Abnormality of the genitourinary system; Abnormality of limbs

Publications

Created: 25 Aug 2019, 7:45 p.m.

Panel version: 2.1015

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Generalized hypotonia
  • Global developmental delay
  • Intellectual disability
  • Unsteady gait
  • Abnormality of the cardiovascular system
  • Abnormality of the genitourinary system
  • Abnormality of limbs
OMIM
600326
Clinvar variants
Variants in DDX6
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

3 Oct 2019, Gel status: 3

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: ddx6 has been classified as Green List (High Evidence).

25 Aug 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

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