Genotype‒phenotype correlation in recessive DNAJB4 myopathy.

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Protein aggregate myopathies arise from pathogenic variants in protein chaperone genes.
• DNAJB4, a heat shock protein-40 (HSP40) family cochaperone, is crucial for cellular proteostasis.
• Recessive DNAJB4 loss-of-function variants cause myopathy with early respiratory failure and spinal rigidity.

Purpose of the Study:

• To investigate the broader clinical and genetic spectrum of DNAJB4 myopathy.
• To identify pathogenic variants in DNAJB4 in patients with unexplained early respiratory failure.
• To establish genotype-phenotype correlations in DNAJB4-related myopathy.

Main Methods:

• Whole-exome sequencing was performed on seven patients with early respiratory failure.
• Five distinct pathogenic DNAJB4 variants (three loss-of-function, two missense) were identified in five families.
• Functional assays, including yeast complementation and TDP-43 disaggregation, were used to assess variant effects.

Main Results:

• Five novel pathogenic DNAJB4 variants were identified in five unrelated families.
• All affected individuals were homozygous for the identified variants.
• Early respiratory failure, rigid spine syndrome, dysphagia, scoliosis, and cardiac dysfunction were common symptoms.
• J-domain missense variants correlated with a more severe phenotype, earlier onset, and higher mortality.

Conclusions:

• DNAJB4 is an emerging cause of myopathy with rigid spine syndrome, exhibiting variable onset and severity.
• Consider DNAJB4 myopathy in individuals with suggestive symptoms, especially neck stiffness or respiratory failure.
• Missense variants in the J domain may predict a more severe clinical presentation and poorer outcomes.