MYL2 – Congenital Fiber-Type Disproportion Myopathy

Recessive loss-of-function variants in MYL2 have been reported in a patient with congenital fiber-type disproportion myopathy (congenital fiber-type disproportion myopathy). Overall, the evidence for this gene–disease association is classified as Limited, based on a single unrelated proband with a homozygous frameshift variant and absence of additional segregating families.

Genetic Evidence

Autosomal recessive inheritance is supported by a homozygous frameshift variant, c.188del (p.Asn63fs), identified in a child with both skeletal muscle fiber-type disproportion and fatal infantile cardiomyopathy. Both parents were heterozygous carriers, but no further affected relatives were reported, yielding no extended segregation beyond the nuclear family (1 proband; 0 additional affected relatives) (PMID:31127036).

Functional Evidence

A separate study of a homozygous cryptic splice-site mutation in MYL2 (c.403-1G>C) showed that the resulting frameshift RLC protein had reduced binding to myosin heavy chain and actin, lower actin-activated ATPase activity, slower cross-bridge kinetics, and decreased maximal contractile force in porcine cardiac muscle preparations—hallmarks of a loss-of-function mechanism consistent with the human phenotype (PMID:27378946).

Conflicting Evidence

No studies to date have refuted the role of recessive MYL2 variants in congenital fiber-type disproportion myopathy.

Integrated Interpretation

Collectively, one AR LoF proband and concordant functional assays support a limited but plausible association between MYL2 and congenital fiber-type disproportion myopathy. Additional unrelated cases and segregation data are needed to bolster the clinical validity.

Key Take-Home: Recessive MYL2 loss-of-function variants are a plausible molecular diagnosis for congenital fiber-type disproportion myopathy, pending further case corroboration.

References

• Cold Spring Harbor Molecular Case Studies • 2019 • MYL2-associated congenital fiber-type disproportion and cardiomyopathy with variants in additional neuromuscular disease genes; the dilemma of panel testing. PMID:31127036
• Frontiers in Physiology • 2016 • Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants. PMID:27378946

Evidence Based Scoring (AI generated)