Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital myopathy

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Dystonin (DST) gene encodes three isoforms: DST-a, DST-b, and DST-e.
• Pathogenic variants in DST are linked to Hereditary Sensory and Autonomic Neuropathy type VI (DST-a) and Epidermolysis bullosa simplex 3 (DST-e).
• Congenital myopathies represent a heterogeneous group of neuromuscular disorders presenting at birth.

Purpose of the Study:

• To investigate the role of DST gene variants in congenital myopathy.
• To identify the specific DST isoforms affected by novel variants.
• To establish genotype-phenotype correlations for DST-associated disorders.

Main Methods:

• Whole exome or genome sequencing in affected individuals.
• RNA and protein analyses in patient-derived cells.
• Muscle biopsy and ultrastructural analysis.
• Genotype-phenotype correlation with existing literature.

Main Results:

• Nine novel biallelic variants in exons 40-41, specific to DST-b, identified in 19 patients with severe neonatal myopathy, arthrogryposis, hypotonia, and dilated cardiomyopathy.
• Seven of these patients died within three years; survivors showed symptom improvement with normal cognition and ambulation.
• Four patients with homozygous variants affecting both DST-a and DST-b presented with severe arthrogryposis and intrauterine or neonatal death, defining a lethal congenital contracture syndrome.
• DST-b variants predominantly affect skeletal muscle and heart, correlating with the observed phenotypes.
• Muscle biopsies showed mild, non-specific myopathic changes and focal myofibrillar disruption.

Conclusions:

• Biallelic variants exclusively affecting DST-b cause autosomal recessive congenital myopathy with variable severity.
• Variants impacting both DST-a and DST-b result in a more severe, lethal congenital contracture syndrome.
• Variant location within DST allows for phenotype prediction, supporting the redefinition of DST as a disease-associated gene with four distinct phenotypes.