SPEG – Centronuclear Myopathy

The association between SPEG and centronuclear myopathy is supported by multiple independent studies with robust clinical and experimental evidence. Autosomal recessive inheritance is consistently observed, with several unrelated probands and segregating affected relatives across different populations (PMID:29614691, PMID:30412272). In one study, a pair of CNM twins were identified with a novel homozygous SPEG variant, and additional case reports have described individuals with either homozygous or compound heterozygous truncating mutations (PMID:31625632).

Genetic evidence includes a wide variant spectrum such as missense, frameshift, and truncating mutations. A representative variant, c.8710A>G (p.Thr2904Ala), has been described in a CNM case and contributes to the genetic support for the association (PMID:31625632). In multiple patients, these variants co‐segregate with the disease phenotype within families, and the cumulative data from these reports have reached ClinGen’s genetic cap for evidence.

Experimental evidence further reinforces this association. In vitro and in vivo functional assays show that SPEG is critical for muscle triad formation and proper calcium homeostasis. Functional studies demonstrate that loss of SPEG disrupts its interaction with key partners such as MTM1, leading to cellular defects consistent with the CNM phenotype (PMID:25087613, PMID:33355670).

Detailed biochemical and cell biological studies have revealed that SPEG deficiency results in abnormal phosphorylation of proteins critical for excitation–contraction coupling. These assays support a mechanism of pathogenicity that likely involves haploinsufficiency and/or dominant-negative effects in muscle cells. Such mechanistic insights provide a direct link between the molecular defect and the clinical manifestation in centronuclear myopathy.

No significant conflicting evidence has emerged in the literature, although the phenotypic spectrum varies. Importantly, while some CNM patients may exhibit additional features such as patent ductus arteriosus, pulmonary arterial hypertension, or ophthalmoplegia, the core myopathic features with centralized nuclei remain the primary diagnostic hallmark linked to SPEG mutations.

In summary, integration of the diverse genetic and functional data positions the SPEG–centronuclear myopathy association as strong. The available evidence, exceeding ClinGen scoring thresholds, provides critical support for diagnostic decision‑making and lays a foundation for targeted clinical management.

Key Take‑home sentence: Identifying pathogenic SPEG variants offers significant clinical utility for early diagnosis and personalized management of patients with centronuclear myopathy.

References

• Journal of neuromuscular diseases • 2018 • Novel SPEG Mutations in Congenital Myopathy without Centralized Nuclei PMID:29614691
• Journal of clinical laboratory analysis • 2020 • Novel SPEG variant cause centronuclear myopathy in China PMID:31625632
• Muscle & nerve • 2019 • Novel SPEG mutations in congenital myopathies: Genotype-phenotype correlations PMID:30412272
• American journal of human genetics • 2014 • SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy PMID:25087613
• Neuromuscular disorders • 2017 • Insights from genotype-phenotype correlations by novel SPEG mutations causing centronuclear myopathy PMID:28624463

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