Genetics of the Congenital Myopathies

Abstract

The congenital myopathies are a heterogeneous group of skeletal muscle disorders characterised by muscle weakness present at birth and typical abnormalities in skeletal muscle fibres, such as protein aggregates, centrally located nuclei or areas lacking mitochondria. Mutations in more than 30 different genes can cause a congenital myopathy. The inheritance can be autosomal dominant, autosomal recessive or X‐linked or sporadic due to novel mutations. The mutated genes can be divided into three groups: genes encoding proteins of the skeletal muscle sarcomere, genes encoding proteins of the sarcoplasmic reticulum and transverse tubules and genes encoding proteins regulating muscle growth and regeneration. The mutations cause impaired or reduced muscle contraction by damaging the contractile machinery or by altering the regulation of muscle contraction, leading to muscle weakness. There is considerable clinical and histological overlap between the different types of congenital myopathies. The inheritance can be autosomal dominant, autosomal recessive or X‐linked or sporadic ( de novo mutations). Disease‐causing variants in more than 30 different genes can cause a congenital myopathy. Disease‐causing variants in the same gene can result in more than one clinical phenotype, and the same clinical phenotype can result from mutations in several different genes. The genes encode proteins essential for skeletal muscle development, muscle contraction, structure and protein turnover.

Recent advances in nemaline myopathy

“…More than 250 disease-causing variants have been published in NEB , making NEB mutations the most common cause of NM [51] . The vast majority of the variants are recessive, and the patients are often compound heterozygous.…”

“…Pathogenic variants in ACTA1 are most commonly de novo dominant missense mutations (90%), and predominantly lead to severe NM by a dominant-negative effect. Autosomal recessive variants (10%), including splice-site, nonsense, frameshift and some missense mutations, result in null alleles [51] . In the transgenic mouse models harbouring known missense variants found in NM patients, the variants strengthened the actin subunit interactions.…”

“…Recessive variants leading to severe NM are more common in TPM3 than in TPM2 . Pathogenic variants in TPM2 usually lead to a milder NM phenotype [51] . In TPM3 , a large homozygous deletion, removing the promoter and the first two exons has been found causing a severe form of NM [74] .…”

“…These indicate that skipping of a larger fragment is likely to be required, further complicating the matter. Moreover, in the case of NEB , very few patients share the same mutation, and the 250 mutations identified to date are dispersed across the entire length of the gene [51] . It is also currently uncertain whether the efficacy of the method is high enough to restore the quantity of functional protein sufficiently to achieve clinically relevant improvement [94] .…”