SPEG is convincingly associated with centronuclear myopathy as an autosomal recessive disorder. Based on multiple independent reports of biallelic SPEG variants in affected individuals with congenital myopathy/CNM phenotypes, together with concordant muscle and animal-model data, the SPEG–centronuclear myopathy relationship is best classified as Strong PMID:25087613, PMID:28624463, PMID:30412272, PMID:31625632. Clinically, SPEG-related disease extends across a congenital myopathy spectrum, but the supplied evidence repeatedly places SPEG within the CNM disease framework.
Human genetic evidence for SPEG in centronuclear myopathy includes 3 unrelated probands in the initial study PMID:25087613, 2 additional unrelated patients with biallelic SPEG variants and CNM/myotubular pathology PMID:28624463, 2 further patients with recessive SPEG mutations in congenital myopathy/CNM cohorts PMID:30412272, and 2 severely affected twins with homozygous SPEG variation reported from China PMID:31625632. Across the supplied CNM-focused literature, this yields at least 9 reported affected individuals from at least 8 families with recessive SPEG-associated myopathy/CNM phenotypes PMID:25087613, PMID:28624463, PMID:30412272, PMID:31625632. The Chinese CNM review also identified SPEG among genetically diagnosed CNM cases in that population, supporting independent recurrence of SPEG in CNM case ascertainment PMID:34595679.
Reported SPEG variants are predominantly predicted loss-of-function alleles, consistent with a recessive loss-of-function mechanism. The supplied CNM-associated SPEG alleles include c.4645dup (p.Ala1549fs), c.3918dup (p.Arg1307fs), c.4321C>T (p.Gln1441Ter), c.7681_7703del (p.Pro2561fs), c.7624C>T (p.Arg2542Ter), c.392C>G (p.Ser131Ter), c.6123_6136dup (p.Pro2046fs), c.6697del (p.Gln2233fs), c.2071C>T (p.Gln691Ter), c.3712C>T (p.Gln1238Ter), c.6697dup (p.Gln2233fs), c.8839C>T (p.Arg2947Ter), c.8270G>T (p.Gly2757Val), c.4276C>T (p.Arg1426Ter), p.Ala972fs, c.6697C>T (p.Gln2233Ter), c.3709_3715+29del, c.9586C>T (p.Arg3196Ter), c.9185_9187del (p.Val3062del), c.2183del (p.Leu728ArgfsTer?), and c.8710A>G (p.Thr2904Ala) PMID:25087613, PMID:28624463, PMID:30412272, PMID:31625632. SPEG missense or in-frame variants have also been described, but the CNM evidence is strongest for biallelic truncating SPEG variants, while some genotype-phenotype variation appears to influence the presence or absence of cardiomyopathy PMID:28624463, PMID:30412272.
The SPEG phenotype is congenital or early onset and includes muscle weakness, hypotonia, and CNM or related congenital myopathy pathology; some individuals show classic centralized nuclei, whereas others have nonspecific congenital myopathy or myotubular-like fibers despite pathogenic SPEG variants PMID:25087613, PMID:28624463, PMID:29614691, PMID:30412272. Additional reported features of SPEG-associated CNM include ophthalmoplegia and respiratory compromise PMID:30412272, as well as facial weakness, arthrogryposis multiplex congenita, patent ductus arteriosus, and pulmonary arterial hypertension in the Chinese twin report with homozygous SPEG c.8710A>G (p.Thr2904Ala) PMID:31625632. Dilated cardiomyopathy is a recurrent comorbidity in several SPEG cases but is not obligatory, which is diagnostically important when interpreting SPEG variants in a neuromuscular setting PMID:25087613, PMID:28624463, PMID:29614691, PMID:30412272.
Functional evidence strongly supports pathogenicity of SPEG deficiency in skeletal muscle. SPEG was identified as an MTM1-interacting protein and this interaction was confirmed by immunoprecipitation and immunofluorescence; in affected human muscle, SPEG protein was markedly reduced or absent in 2 tested individuals PMID:25087613. Speg-knockout mice show increased central nuclei in muscle, providing direct phenotype concordance with human CNM PMID:25087613. Additional work showed that SPEG binds desmin and that SPEG deficiency disrupts triad and focal adhesion proteins, with reduced RyR1 and abnormal localization of multiple triadic proteins in Speg-knockout muscle PMID:33355670. Multi-omics and mechanistic studies further linked SPEG to myospryn complex components, RyR1 phosphorylation, and broader triad biology PMID:38725372, and DNM2 reduction partially rescued skeletal myopathy phenotypes in a SPEG-deficient mouse model, supporting disease relevance of the observed pathway disruption PMID:35763354.
The main limitation is phenotypic breadth: not every individual with biallelic SPEG variants had classic CNM histology, and some reports emphasized congenital myopathy without centralized nuclei or predominant cardiomyopathy, indicating that SPEG causes a broader striated-muscle disorder spectrum rather than a perfectly uniform CNM presentation PMID:29614691, PMID:30412272. Segregation detail is limited in the supplied summaries, and no formal case-control enrichment data were provided. No conflicting evidence was provided in the supplied dataset.
Overall, the supplied evidence supports SPEG as a clinically valid autosomal recessive cause of centronuclear myopathy, often accompanied by congenital myopathy features and variably by cardiomyopathy. The combination of repeated biallelic SPEG findings across independent families, a predominantly truncating SPEG variant spectrum, and concordant reduction or loss of SPEG function in human tissue and mouse models supports routine consideration of SPEG in CNM/congenital myopathy diagnostic testing panels PMID:25087613, PMID:28624463, PMID:30412272, PMID:31625632. Key take-home: SPEG is a strong autosomal recessive centronuclear myopathy gene, especially when biallelic loss-of-function variants are identified in patients with congenital muscle weakness, hypotonia, CNM or myotubular pathology, and possible associated cardiomyopathy.
Gene–Disease AssociationStrongMultiple independent reports describe at least 8 families with recessive SPEG variants and CNM/congenital myopathy phenotypes, supported by concordant human muscle and mouse-model data. Genetic EvidenceStrongRepeated biallelic SPEG variants across independent probands, predominantly truncating alleles, with recurrent CNM-associated phenotypes and some familial recurrence. Functional EvidenceStrongReduced or absent SPEG in patient muscle, MTM1 interaction, CNM-like central nuclei in Speg-knockout mice, triad/focal adhesion defects, and rescue of skeletal myopathy with DNM2 reduction. |