Childhood onset dystonia, chorea or related movement disorder

Gene: COL6A3

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 19 Jun 2022, 11:23 p.m. | Last Modified: 19 Jun 2022, 11:23 p.m.

Panel Version: 1.237

I don't know

The mode of inheritance of this gene has been updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 30 Jan 2023, 6:27 p.m. | Last Modified: 30 Jan 2023, 6:27 p.m.

Panel Version: 2.10

Associated with Dystonia 27 MIM#616411 (AR) in OMIM and Gene2Phenotype (confirmed, biallelic)

PMID: 26004199 - Zech et al 2015 - using WES to analyse a German family with recessive isolated dystonia they identified disease-segregating compound heterozygous mutations in COL6A3 in 2 siblings. Screening of exons 41 and 42 in 367 more families resulted in the identification of two additional recessive German pedigrees with compound heterozygous mutations in COL6A3 (family 2 had 2 affected siblings, family 3 has 1 affected child). All affected individuals had at least one pathogenic allele in exon 41. 5 variants found
c.9128G>A [p.Arg3043His] - family 1 (exon 41)
c.9245C>G [p.Pro3082Arg] - family 1
c.8966−1G>C (p.Val2989_Lys3077delinsGlu) - family 2 and family 3 (exon 41)
c.7502G>A (p.Arg2501His) - family 2
c.7660G>A (p.Ala2554Thr) - family 3

They note that in the ExAC dataset, the c.9128G>A (p.Arg3043His) variant and the c.9245C>G (p.Pro3082Arg) variant were each reported in two South Asian exomes in the homozygous state. These homozygous alleles may display reduced penetrance or that the two homozygote subjects have or will develop dystonia, which could manifest in late adolescence or young adulthood and might be of only moderate severity. The c.9245C>G (p.Pro3082Arg) appears with a frequency of 0.001 in the European ExAC population. They note the it is likely there are several carriers for recessive disorders in the general population.

PMID: 26687111 - Jochim et al 2016 - further characterise the clinical phenotype of the 5 patients from Zech et al 2015.

PMID: 26872670 - Lohmann et al 2016 - assessed by direct sequencing the frequency of rare variants in Exons 41 and 42 of COL6A3 in 955 patients with isolated or combined dystonia or with another movement disorder with dystonic features. They found 1 patient with two variants in COL6A3 (Thr732Met + Pro3082Arg) but the COL6A3 mutations did not segregate with the disease in four affected siblings. The patient had been diagnosed with Parkinson´s disease (with dystonic posturing) due to homozygous PINK1 mutations. The authors argue that their data do not support a pathogenic role of compound heterozygous COL6A3 mutations in dystonia. They suggest that the occurrence of presumably compound heterozygous mutations may be a chance finding in dystonia patients.

PMID: 32037012 - Panda and Sharawat 2020 - report a new case of COL6A3 mutation associated early-onset isolated dystonia-DYT27 in an 8 year old boy. Compound heterozygous variants in exons 10 and 12 found (p.Gly1517Ser and p.Pro1894Leu). The parents were heterozygous carriers of the variants. The two variants have not been reported in the 1000 genomes and ExAc (Exome Aggregation Consortium).

Created: 18 Aug 2020, 10:09 p.m. | Last Modified: 18 Aug 2020, 10:09 p.m.

Panel Version: 1.45

I don't know

Three unrelated German families reported initially. Onset of segmental isolated dystonia involving the face, neck, bulbar muscles, and upper limbs at age 20 years. All patients carried mutations affecting the C terminus, with at least 1 mutation specifically affecting exon 41. Note recent report of bi-allelic variants in exon 10 and 12 however (PMID: 32037012) and also PMID: 26872670 which calls into question this gene-disease association, due in part to presence of two homozygotes for the p.Pro3082Arg variant in gnomad.

Created: 28 Mar 2020, 9:49 p.m. | Last Modified: 28 Mar 2020, 9:49 p.m.

Panel Version: 1.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Dystonia 27, MIM#616411

Publications

• 26004199
• 32037012
• 26872670

Comment on mode of inheritance: Changed MOI from recommendation from Specialist Test Group (via Robyn Labrum LNGLH)

Created: 12 Dec 2019, 1:45 p.m. | Last Modified: 12 Dec 2019, 1:45 p.m.

Panel Version: 0.255

Green List (high evidence)

Suggested by Huw and Raquel

Created: 9 Jul 2019, 4:24 p.m. | Last Modified: 9 Jul 2019, 4:24 p.m.

Panel Version: 0.9