Skeletal dysplasia
Gene: DVL2
The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 2:18 p.m. | Last Modified: 30 Jan 2023, 2:33 p.m.
Panel Version: 3.5
Comment on list classification: Promoting from grey to amber, but with a recommendation for consideration for GREEN rating following GMS review. Although only 1 case has been reported, supporting evidence comes from canine data and from the fact that similar causative variants associated with Robinow syndrome have been found in the other two Dishevelled paralogs.Created: 13 Apr 2022, 4:52 p.m. | Last Modified: 13 Apr 2022, 4:52 p.m.
Panel Version: 2.202
Not associated with any phenotype in OMIM or Gene2phenotype.
As Michael Oldridge notes PMID:35047859 (Zhang et al 2021) report a patient with Robinow syndrome and a de novo 1-bp duplication in exon 15 of DVL2 .
Other supporting information:
PMID:33599851 (Niskanen et al 2021) and PMID: 30521570 (Mansour et al 2018) report that a homozygous frameshift deletion variant in DVL2 is associated with a truncated, kinked tail (caudal vertebral malformations) in English Bulldogs, French Bulldogs and Boston Terriers . They also note that these breeds are characterized by traits such as a wide head, flat face and short-limbed dwarfism, which are characteristic of Robinow syndrome in humans.Created: 13 Apr 2022, 4:48 p.m. | Last Modified: 13 Apr 2022, 4:48 p.m.
Panel Version: 2.200
Publications
De novo fs variant in final exon of DVL2 identified in patient with clinical diagnosis of Robinow syndrome. This leads to a 103 residue missense tail extending beyond the WT stop codon. A number of similar fs variants have been identified in DVL1 and DVL3 leading to autosomal dominant Robinow syndrome; these variants also lead to extended missense tails and are therefore thought to act via a very specific gain of function mechanism (LOF variants in these genes do not lead to Robinow). DVL1, 2 and 3 share considerable homology (59-67%) and have overlapping function during development.
Only reported in 1 case but the very specific nature of the mutation explains rareity. Should be tested as Green.
Sources: Expert ReviewCreated: 18 Mar 2022, 2:07 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
autosomal dominant Robinow sydrome
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Tag gene-checked tag was added to gene: DVL2.
Tag Q2_21_NHS_review was removed from gene: DVL2. Tag Q2_22_rating was removed from gene: DVL2. Tag Q2_22_expert_review was removed from gene: DVL2.
Source Expert Review Green was added to DVL2. Source NHS GMS was added to DVL2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: dvl2 has been classified as Amber List (Moderate Evidence).
Tag Q2_22_expert_review tag was added to gene: DVL2.
Publications for gene: DVL2 were set to PMID: 35047859
Tag Q2_21_NHS_review tag was added to gene: DVL2. Tag Q2_22_rating tag was added to gene: DVL2.
Phenotypes for gene: DVL2 were changed from autosomal dominant Robinow sydrome to autosomal dominant Robinow sydrome; Robinow syndrome, MONDO:0019978
gene: DVL2 was added gene: DVL2 was added to Skeletal dysplasia. Sources: Expert Review Mode of inheritance for gene: DVL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DVL2 were set to PMID: 35047859 Phenotypes for gene: DVL2 were set to autosomal dominant Robinow sydrome Penetrance for gene: DVL2 were set to Complete Mode of pathogenicity for gene: DVL2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: DVL2 was set to GREEN