Like father, like son: RNA-sequencing from a 30-year-old muscle biopsy identifies a novel splice variant in ACTA1 as the cause of an attenuated nemaline myopathy phenotype

ACTA1-related nemaline myopathy is a disorder typically presenting in the neonatal period, but later-onset cases have been described. The majority of patients carry de novo missense variants. We report a father and son with shared features of early-onset, but mild myopathic symptoms, including gross motor delay and facial weakness. Muscle biopsies showed nemaline rods. Genetic testing identified a novel splice variant in ACTA1 (c.809–10C>A). RNA-sequencing was performed on muscle, including the father’s sample which had been archived for 31 years; both showed retention of intron 5 in ∼20 % of transcripts, predicted to cause protein truncation, but not nonsense mediated decay. In vitro studies showed that the variant leads to the formation of ACTA1 aggregates. These findings provide functional support for the variant’s pathogenicity in dominantly inherited nemaline myopathy and rationale for the attenuated phenotype. This case highlights the utility of muscle biopsy and RNA-sequencing in the diagnosis of nemaline myopathy.