STAC3 – Bailey-Bloch Congenital Myopathy

STAC3 has been robustly associated with Bailey-Bloch congenital myopathy (MONDO_0009722), an autosomal recessive disorder characterized by congenital muscle weakness, flexion contractures, and short stature. Multiple independent case reports and multi‐patient studies have identified biallelic pathogenic variants in STAC3 in affected individuals, with segregation observed in at least two families (PMID:28777491). In one study, a non-Amerindian patient was found to be compound heterozygous for STAC3 mutations, including the frameshift variant c.862A>T (p.Lys288Ter), which was accompanied by clinical findings such as flexion contractures and short stature (PMID:28411587).

Genetic evidence is strengthened by the identification of diverse variant classes—including missense and frameshift mutations—across unrelated probands. For example, additional case series have reported the recurrent p.Trp284Ser allele and compound heterozygous changes in STAC3, with segregation data supporting the autosomal recessive inheritance pattern (PMID:36030003 and PMID:37626540).

Functional validation studies have further corroborated the clinical relevance of STAC3 variants. Experimental assays using electrophysiological recordings, Ca²⁺ imaging, and protein–protein interaction studies demonstrate that mutations in STAC3 impair excitation–contraction coupling in skeletal muscle, an effect that mirrors the clinical phenotype (PMID:23736855 and PMID:28112192).

Despite some phenotypic overlap with other neuromuscular disorders, the combined genetic and functional data present a coherent picture that supports a strong gene–disease relationship. Notably, while additional rare variants in STAC3 have been reported, the current evidence in multiple unrelated individuals exceeds the typical ClinGen scoring maximum.

Key take‑home sentence: STAC3 variant screening should be integrated into the diagnostic work‑up for congenital myopathy patients given its robust genetic and functional association with Bailey-Bloch congenital myopathy.

References

• American journal of medical genetics. Part A | 2017 | Identification of STAC3 variants in non‑Native American families with overlapping features of Carey‑Fineman‑Ziter syndrome and Moebius syndrome PMID:28777491
• Neuropediatrics | 2017 | Novel STAC3 Mutations in the First Non‑Amerindian Patient with Native American Myopathy PMID:28411587
• European journal of medical genetics | 2022 | STAC3 related congenital myopathy: A case series of seven Comorian patients PMID:36030003
• Brain sciences | 2023 | Bailey‑Bloch Congenital Myopathy in Brazilian Patients: A Very Rare Myopathy with Malignant Hyperthermia Susceptibility PMID:37626540
• Nature communications | 2013 | Stac3 is a component of the excitation‑contraction coupling machinery and mutated in Native American myopathy PMID:23736855
• Scientific reports | 2017 | STAC3 stably interacts through its C1 domain with CaV1.1 in skeletal muscle triads PMID:28112192

Evidence Based Scoring (AI generated)