STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility

STAC3 is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, the authors describe 18 patients carrying STAC3 pathogenic variants, the largest cohort of patients with STAC3-related congenital myopathy studied up to now. Importantly, the patients investigated here were not of Native American origin. Seventeen patients, of African, Middle Eastern, Afro-Caribbean, Comorian and South American descent, carried the previously described homozygous NAM p.Trp284Ser STAC3 variant and one patient, of African/Afro-Caribbean descent, was compound heterozygous for the NAM variant in one allele and a novel c.997-1G>T splice site variant in the other allele. Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A Malignant Hyperthermia (MH) -like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl induced membrane depolarisation resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported.

Zaharieva IT, Sarkozy A, Munot P, et al. STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. Hum Mutat. 2018 Aug 31. [Epub ahead of print]