Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies
Gene: DAG1Comment on mode of inheritance: Confirmed in OMIM for relevant phenotype.Created: 28 Nov 2019, 5:11 p.m. | Last Modified: 28 Nov 2019, 5:11 p.m.
Panel Version: 1.157
Comment on list classification: Promoted from Red to Green due to overall reviews and clinical comments from GLH representatives.Created: 28 Nov 2019, 5:10 p.m. | Last Modified: 28 Nov 2019, 5:10 p.m.
Panel Version: 1.156
Review and rating from Natalie Forrester (SWGLH - Bristol Genetics) on behalf of South West GLH for GMS Neurology specialist test group.Created: 30 Apr 2019, 11:45 a.m.
PubMed: 25503980 - 7-year-old Japanese boy with a very mild form of MDDGC9 presenting only as asymptomatic increased serum creatine kinase. Identified compound heterozygous missense mutations by WES. In vitro functional expression studies indicated that the mutations did not influence expression of dystroglycan, but did cause a defect in posttranslational modification. One variant is 0.013% (including 1 homoz) and other 0.2% (603 alleles including 1 homoz) in gnomAD - probably too common. PMID: 29036200 - some functional evidence for missense variants identified in paper above but considering MAF this should be used with caution. PubMed: 21388311 - mice with a homozygous T190M mutation in the Dag1 gene, which corresponds to the human T192M mutation, developed muscular dystrophy and neurologic motor impairment. Homoz vlimb-girdle muscular dystrophy-dystroglycanopathy and cognitive impairmentariant, absent from gnomAD and in patient withCreated: 30 Apr 2019, 11:24 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9, 613818
Publications
Note that an international expert review of the LGMD genes and nomenclature deemed that this is an LGMD causative gene (PMID: 30055862), I therefore strongly feel that this should be included in this panel listCreated: 29 Mar 2019, 1:11 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Limb girdle muscular dystrophy; congenital muscular dystrophy
Publications
Variants in this GENE are reported as part of current diagnostic practice
Listed as associated with Limb Girdle Muscular Dystrophy by Gene Advisor (June 2016), Steve AbbsCreated: 27 Jul 2016, 8:21 a.m.
Comment on phenotypes: Also associated with Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9, 616538Created: 26 Jul 2016, 2:08 p.m.
Comment when marking as ready: Associated with phenotype in OMIM and G2P. Found in 2/4 sources. Expert reviewer recommends Amber. There are a total of three variants reported (could not find any more in the literature), one is found as a homozygote and the other two as compound heterozygotes in one patient. Functional studies done on the latter two variants.
Comment from Emma Clement: probably not sufficient evidence for green status (yet) although feel that very likely to be more LGMD mutations reported in this gene . Pains me to leave it orange as this is a really interesting gene. We searched for ages (research) for mutations in this gene, never found one, hopefully exome will turn up more.
appear to be rare.Created: 9 Jun 2016, 12:39 p.m.
Comment on mode of inheritance: One patient reported as homozygous for one variant and another reported as a compound heterozygous for two additional variantsCreated: 9 Jun 2016, 10:12 a.m.
Comment on list classification: Definitely causes a more severe muscular dystrophy; evidence for LGMD phenotype less convincing.Created: 29 May 2016, 3:31 p.m.
Gene: dag1 has been classified as Green List (High Evidence).
Mode of inheritance for gene: DAG1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Gene: dag1 has been classified as Green List (High Evidence).
Source Yorkshire and North East GLH was added to DAG1.
Phenotypes for gene: DAG1 were changed from Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9, 613818; Limb girdle muscular dystrophy; congenital muscular dystrophy to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9, 613818; Limb girdle muscular dystrophy; congenital muscular dystrophy; Limb-girdle muscular dystrophy
Publications for gene: DAG1 were set to 21388311; 25503980; 25503980; 29036200; 21388311; 14678799
Phenotypes for gene: DAG1 were changed from Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9, 613818 to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9, 613818; Limb girdle muscular dystrophy; congenital muscular dystrophy
Publications for gene: DAG1 were set to 21388311; 25503980; 25503980; 29036200; 21388311; 14678799
Publications for gene: DAG1 were set to 21388311; 25503980
Source NHS GMS was added to DAG1.
Source South West GLH was added to DAG1.
Comments from Fiona Karet included. A Green review for each gene relevant for this panel on the Gene Advisor download has been included.
Phenotypes for DAG1 were set to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9, 613818
This gene has been classified as Red List (Low Evidence).
This gene has been classified as Amber List (Moderate Evidence).
This gene has been classified as Amber List (Moderate Evidence).
This gene has been classified as Green List (High Evidence).
Mode of inheritance for DAG1 was changed to BIALLELIC, autosomal or pseudoautosomal
Publications for DAG1 were set to 21388311; 25503980
Phenotypes for DAG1 were set to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9, 613818; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9, 616538
This gene has been classified as Amber List (Moderate Evidence).
DAG1 was added to Limb girdle muscular dystrophypanel. Sources: Radboud University Medical Center, Nijmegen,Emory Genetics Laboratory
DAG1 was added to Limb girdle muscular dystrophypanel. Sources: Radboud University Medical Center, Nijmegen,Emory Genetics Laboratory