Activation of cryptic donor splice site due to an exonic MYPN variant in congenital myopathy

Biallelic pathogenic variants in the MYPN gene are a known cause of congenital myopathy, and exonic variants that activate cryptic splice sites have not been previously reported. Here, we report a Chinese proband with congenital myopathy carrying a homozygous nonsense variant, c.2986C>T (p.Arg996Ter), in exon 14 of the MYPN gene. Transcriptional analysis suggested that this variant likely activated a cryptic donor splice site, truncating the last 91 nucleotides of exon 14 during pre-mRNA splicing. Western blotting and immunofluorescence confirmed a deficiency of myopalladin protein in the proband’s skeletal muscle. Our study highlights that exonic variants, particularly those distant from exon-intron junctions, can induce aberrant pre-mRNA splicing. This insight is crucial for interpreting the pathogenicity of variants of uncertain significance and enhancing diagnostic yield in genetic testing.