A Titin Truncating Variant Causing a Dominant Myopathy With Cardiac Involvement in a Large Family: The Exception That Proves the Rule.

Background: Titin truncating variants (TTNtvs) have been repeatedly reported as causative of recessive but not dominant skeletal muscle disorders.

Objective: To determine whether a single heterozygous nonsense variant in can be responsible for the observed dominant myopathy in a large family.

Methods: In this case series, all available family members (8 affected and 6 healthy) belonging to a single family showing autosomal dominant inheritance were thoroughly examined clinically and genetically.

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene.

Variant Associated With a Myalgic Myopathy Phenotype.

Background And Objectives: This study aimed to characterize the phenotype of a novel myalgic myopathy encountered in a Finnish family.

Methods: Four symptomatic and 3 asymptomatic individuals from 2 generations underwent clinical, neurophysiologic, imaging, and muscle biopsy examinations. Targeted sequencing of all known myopathy genes was performed.

Extension of the DNAJB2a isoform in a dominant neuromyopathy family.

Recessive mutations in the DNAJB2 gene, encoding the J-domain co-chaperones DNAJB2a and DNAJB2b, have previously been reported as the genetic cause of progressive peripheral neuropathies, rarely involving pyramidal signs, parkinsonism and myopathy. We describe here a family with the first dominantly acting DNAJB2 mutation resulting in a late-onset neuromyopathy phenotype. The c.

HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies.

Chaperone-assisted selective autophagy (CASA) is a highly selective pathway for the disposal of misfolding and aggregating proteins. In muscle, CASA assures muscle integrity by favoring the turnover of structural components damaged by mechanical strain. In neurons, CASA promotes the removal of aggregating substrates.