MYL1 – Congenital Myopathy

Congenital myopathies are clinically heterogeneous disorders characterized by early onset hypotonia, muscle weakness and distinctive histopathological features. Among these, the absence or selective atrophy of type II myofibers is a hallmark in some patients. Recent exome sequencing has identified bi-allelic variants in MYL1 associated with a severe congenital myopathy. MYL1 encodes the skeletal muscle fast-twitch specific myosin essential light chain (ELC), which is critical for myosin motor stability and muscle contraction. Loss of function of ELC impairs myofiber development and function. Here, we summarize the genetic and functional evidence supporting MYL1 involvement in this disease.

Exome sequencing of two unrelated consanguineous families revealed homozygous MYL1 variants in probands diagnosed with congenital myopathy ([PMID:30215711]). Proband 1 harbored a homozygous essential splice acceptor variant, c.479-2A>G, predicted to cause exon 5 skipping. Proband 2 carried a homozygous missense substitution, c.488T>G (p.Met163Arg). These variants were absent or extremely rare in population databases. Segregation analysis demonstrated inheritance from unaffected carrier parents with no additional affected relatives reported. The identification of two unrelated probands with compatible phenotypes provides limited genetic evidence but supports disease association.

MYL1-related congenital myopathy follows an autosomal recessive inheritance pattern. The variant spectrum comprises loss-of-function through splice-disrupting alleles and missense substitutions affecting protein stability. The c.479-2A>G splice variant is predicted to abolish normal splicing and remove critical structural elements of ELC. The recurrent missense change p.Met163Arg affects a conserved residue within the IQ-binding domain of myosin heavy chain. The exclusive occurrence of homozygous variants and absence of heterozygous affected individuals argue against dominant-negative effects. Population allele frequencies are consistent with a rare recessive disorder.

Immunoblot and histological analyses showed markedly reduced MYL1 protein in muscle biopsies from both probands, indicating protein instability or degradation ([PMID:30215711]). In silico protein modelling of p.Met163Arg predicted disrupted interactions with the IQ domain of myosin heavy chain. Functional knockdown of myl1 in zebrafish embryos recapitulated key disease features, including abnormal muscle morphology, disrupted myofiber architecture and impaired touch-evoked escape responses. These findings confirm that ELC deficiency disrupts fast-twitch muscle development and function in vivo. Concordance between human tissue data and animal models provides strong experimental support. The mechanism is consistent with loss of function leading to severe congenital myopathy.

No conflicting reports have been published to date. The absence of heterozygous individuals with a phenotype and the reproducible animal model phenotype strengthen the causal link. Both splice and missense alleles lead to reduced or unstable protein, consistent with a loss-of-function mechanism. Genetic and functional evidence together meet ClinGen moderate-level clinical validity criteria. Incorporation of MYL1 into genetic testing panels will improve diagnostic yield for congenital myopathies with type II fiber involvement. Additional cohort studies may further refine phenotype-genotype correlations.

Overall, the accumulated genetic and functional data support a moderate clinical validity classification for the MYL1–congenital myopathy association. Key Take-home: Biallelic MYL1 variants cause a severe autosomal recessive congenital myopathy characterized by type II fiber atrophy, and MYL1 should be included in diagnostic muscle disease gene panels.

References

• Human Molecular Genetics • 2018 • Bi-allelic mutations in MYL1 cause a severe congenital myopathy. PMID:30215711

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