Genotype-phenotype correlation in recessive DNAJB4 myopathy.

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Protein aggregate myopathies can arise from pathogenic variants in protein chaperone genes.
• DNAJB4, a heat shock protein-40 (HSP40) cochaperone, is crucial for cellular proteostasis.
• Recessive loss-of-function variants in DNAJB4 are known to 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 genetic variants in DNAJB4 associated with early respiratory failure of unknown etiology.
• To establish genotype-phenotype correlations in DNAJB4 myopathy.

Main Methods:

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

Main Results:

• Five novel pathogenic DNAJB4 variants (three nonsense, two missense) were identified in homozygous individuals.
• All patients presented with early respiratory failure; some also exhibited rigid spine syndrome, dysphagia, contractures, scoliosis, neck stiffness, and cardiac dysfunction.
• J-domain missense variants correlated with a more severe phenotype, earlier onset, and higher mortality, while nonsense variants showed decreased stability.

Conclusions:

• DNAJB4 is an emerging cause of myopathy with rigid spine syndrome, presenting with variable onset and severity.
• The study identified a strong genotype-phenotype correlation, with J-domain missense variants predicting a more severe disease course.
• DNAJB4 myopathy should be considered in individuals with suggestive symptoms, especially those with infantile neck stiffness or adult respiratory failure without significant limb weakness.