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<p>Biallelic pathogenic variants in <i>DNAJB4</i>, encoding a heat shock protein 40 (Hsp40) family co-chaperone, have been recently associated with congenital myopathy 21 with early respiratory failure (OMIM 620326). The typical phenotype involves childhood onset, rigid spine, and progressive respiratory insufficiency. However, phenotypic variability has been increasingly recognized. We describe a 25-year-old woman with a four-year history of progressive proximal lower limb weakness, lumbar lordosis, bilateral calf prominence, and waddling gait. Notably, she had no overt respiratory symptoms at presentation, with a mild restrictive abnormality on pulmonary function testing. MRI revealed selective hamstring involvement. Genetic testing identified a novel homozygous nonsense variant in <i>DNAJB4</i> (NM_007034.5:c.343&#xa0;C &gt; T, p.Arg115Ter), located in exon 2 (chr1:78013182), classified as likely pathogenic (ACMG: PVS1, PM2, PP4). This case expands the spectrum of <i>DNAJB4</i>-related myopathy by highlighting an adult-onset limb-girdle phenotype without clinical respiratory symptoms at presentation, despite a homozygous truncating variant. However mild/subclinical respiratory abnormalities should be detected early and followed longitudinally, given that recessive DNAJB4 myopathy shows variable onset (including adult onset) and respiratory failure can emerge over time. Recognition of such variability is important for prognosis, counselling, and future therapeutic trials.</p>

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Adult-onset DNAJB4-related limb-girdle myopathy—expanding the phenotypic spectrum

  • 期刊论文

  • 发表日期：

    2026年3月16日

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  • Subhajit Roy,
  • Saraswati Nashi,
  • Deepak Menon,
  • Seena Vengalil,
  • Atchayaram Nalini

摘要

Biallelic pathogenic variants in DNAJB4, encoding a heat shock protein 40 (Hsp40) family co-chaperone, have been recently associated with congenital myopathy 21 with early respiratory failure (OMIM 620326). The typical phenotype involves childhood onset, rigid spine, and progressive respiratory insufficiency. However, phenotypic variability has been increasingly recognized. We describe a 25-year-old woman with a four-year history of progressive proximal lower limb weakness, lumbar lordosis, bilateral calf prominence, and waddling gait. Notably, she had no overt respiratory symptoms at presentation, with a mild restrictive abnormality on pulmonary function testing. MRI revealed selective hamstring involvement. Genetic testing identified a novel homozygous nonsense variant in DNAJB4 (NM_007034.5:c.343 C > T, p.Arg115Ter), located in exon 2 (chr1:78013182), classified as likely pathogenic (ACMG: PVS1, PM2, PP4). This case expands the spectrum of DNAJB4-related myopathy by highlighting an adult-onset limb-girdle phenotype without clinical respiratory symptoms at presentation, despite a homozygous truncating variant. However mild/subclinical respiratory abnormalities should be detected early and followed longitudinally, given that recessive DNAJB4 myopathy shows variable onset (including adult onset) and respiratory failure can emerge over time. Recognition of such variability is important for prognosis, counselling, and future therapeutic trials.