Gene/protein: SPEG (striated muscle-enriched protein kinase) encodes a large protein kinase expressed in striated muscle with important roles in muscle cell development, sarcomere organization and excitation-contraction (E-C) coupling. SPEG has been shown to interact with myotubularin (MTM1) and other muscle proteins critical for myofiber maintenance.
Variant types: Reported pathogenic variants include truncating (nonsense, frameshift), canonical splice-site, small indels, missense variants and larger deletions. Multiple reported pathogenic alleles in the literature are truncating or predicted loss-of-function.
Mechanism: SPEG deficiency impairs normal muscle structure and function, likely through perturbed interaction with MTM1 and dysregulation of pathways critical to Z-line and triad development; loss-of-function is a major mechanism for many severe congenital cases.
Diagnostic testing: Diagnostic testing is usually by targeted gene panel for congenital myopathy, cardiomyopathy panels, or exome/genome sequencing. When a variant of uncertain significance is found, correlate with clinical phenotype and consider segregation testing, muscle pathology and functional evaluation where possible. Interpretation should consider isoform expression (SPEG is large with multiple transcripts) and variant effect on protein domains.
Genotype–phenotype correlations: Biallelic truncating and loss-of-function genotypes are frequently associated with severe congenital myopathy and early cardiac involvement. Some missense alleles are associated with isolated myopathy or milder phenotypes; case series (Qualls et al. 2019, Wang et al. 2017) expand the range of observed phenotypes.
SPEG