Novel MYL1 Intron Variant With Expanded Phenotype

Congenital myopathy-14 (CMYO14) is an ultrarare autosomal recessive disorder caused by biallelic variants in MYL1, with only four patients reported to date. We describe what is likely the fifth reported patient, a neonate with severe hypotonia, respiratory insufficiency, and skeletal anomalies showing distinct histological changes of skeletal muscle consistent with all previously described patients. The patient carried a novel homozygous intron variant (c.479-25T>C, p.(?)) in MYL1. RNA analysis of patient muscle demonstrated aberrant splicing, with inclusion of 19 bp from intron 4 in most transcripts, resulting in a frameshift and premature stop codon, and in-frame skipping of exons 4–5 in a minority of transcripts encompassing functional domains. In addition to core CMYO14 features, the patient presented with craniofacial anomalies not previously described. This case broadens the genotypic and phenotypic spectrum of MYL1-related disease and underscores the diagnostic importance of intron variants, highlighting the value of combining in silico splice prediction with functional RNA analyses.