Arthrogryposis

Gene: DST

Green List (high evidence)

Comment on list classification: Promoting to amber but with a recommendation for green rating following GMS review since there are sufficient cases with plausible disease causing variants and an appropriate phenotype.

Created: 30 Sep 2025, 5:19 p.m. | Last Modified: 30 Sep 2025, 5:19 p.m.

Panel Version: 6.36

Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively. However, variants in the DTS-b isoform appear to result in a different phenotype.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.

Created: 30 Sep 2025, 5:18 p.m. | Last Modified: 2 Oct 2025, 12:20 p.m.

Panel Version: 9.10

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952

Publications

• 40497796
• 35942699

Green List (high evidence)

9 affected individuals from 14 unrelated families, with variants in exons 40-41, specific to the DST-b isoform expressed in muscle.

Phenotype: "severe neonatal myopathy characterized by arthrogryposis, hypotonia, and dilated cardiomyopathy"
Sources: Literature

Created: 7 Aug 2025, 4:21 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 40497796