| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Muscular dystrophy and myopathy_Paediatric v1.96 | DST | Zornitza Stark Marked gene: DST as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Muscular dystrophy and myopathy_Paediatric v1.96 | DST | Zornitza Stark Gene: dst has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Muscular dystrophy and myopathy_Paediatric v1.96 | DST | Zornitza Stark Phenotypes for gene: DST were changed from congenital myopathy MONDO:0019952 to congenital myopathy MONDO:0019952, DST-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Muscular dystrophy and myopathy_Paediatric v1.95 | DST | Chirag Patel Classified gene: DST as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Muscular dystrophy and myopathy_Paediatric v1.95 | DST | Chirag Patel Gene: dst has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Muscular dystrophy and myopathy_Paediatric v1.94 | DST |
Chirag Patel gene: DST was added gene: DST was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DST were set to PMID: 40497796 Phenotypes for gene: DST were set to congenital myopathy MONDO:0019952 Review for gene: DST was set to GREEN Added comment: Dystonin (DST) encodes three major isoforms, DST-a, DST-b, and DST-e. Biallelic pathogenic variants in DST are associated with Hereditary Sensory and Autonomic Neuropathy type VI (caused by a loss of DST-a) and Epidermolysis bullosa simplex 3 (caused by a loss of DST-e). PMID 40497796 reports 19 affected individuals from 14 unrelated families with severe congenital myopathy characterized by arthrogryposis, hypotonia, myopathy, and motor delay. 3/19 resulted in TOP, 9/14 needed CPAP ventilation, 7/14 had dilated cardiomyopathy, 7/16 died under 3 years of life. 3 patients are now over 25 years with normal cognition and ambulation. Muscle biopsies in 4 patients (aged 1 month to 3 years) showed mild/non-specific myopathic changes, mild/focal myofibrillar disruption, and non-specific undulating nuclear membranes. WES/WGS identified 9 different LOF variants in biallelic state located in exons 40-41 and specific to isoform DST-b. 18/19 individuals had homozygous variants, 1/19 individuals had compound heterozygous variants, 8/9 variants were in exon 40, 1/9 variants were in exon 41. RNA analyses demonstrated that transcripts encoding DST-b are predominantly expressed in skeletal muscle, heart tissue, and cultured fibroblasts, but not in brain matching the phenotypic spectrum. Patient-derived fibroblasts exhibited reduced DST mRNA expression. Proteomic analysis confirmed a reduction of DST protein levels due to an absence of the DST-b isoform. Therefore, biallelic variants exclusively affecting DST-b cause an autosomal recessive congenital myopathy. Additionally, 2 homozygous LOF variants (outside of exons 40-41) affecting both DST-a and DST-b isoforms were found in 4 patients from 2 unrelated families with severe arthrogryposis and death in utero or shortly after birth. Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome. Sources: Literature |
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