Heterozygous loss-of-function variants in SPTAN1 cause an early childhood onset distal myopathy.

Purpose: Heterozygous pathogenic variants in SPTAN1 cause a diverse spectrum of neurogenetic disorders ranging from peripheral and central nervous system involvement to complex syndromic presentations. We set out to investigate the role of SPTAN1 in genetically unsolved hereditary myopathies.

Methods: Through international collaboration we identified 14 families with distal weakness and heterozygous SPTAN1 loss-of-function variants. Clinical data, electrophysiology, muscle CT or MRI and muscle biopsy findings were collected and standardized. SPTAN1 protein, mRNA expression analysis and cDNA sequencing was performed on muscle tissue from two participants.

Results: Five families showed autosomal dominant mode of inheritance, while in nine patients the variant was shown to be de novo, including 2 pairs of monozygotic twins. In two families, further segregation analysis was not possible. All affected participants presented with early childhood onset distal weakness and foot abnormalities. Muscle MRI or CT in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes in 7 patients. Finally, we provide proof for nonsense mediated decay in muscle tissue derived from two patients.

Conclusion: We present evidence linking heterozygous SPTAN1 loss-of-function variants to childhood-onset distal myopathy in 14 unrelated families.