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Background <p>Dysferlinopathies are autosomal recessive neuromuscular disorders caused by pathogenic variants in the <i>DYSF</i> gene, most commonly presenting as limb-girdle muscular dystrophy type R2 (LGMD R2). In this study, we investigated a non-consanguineous Tunisian family with a classical proximal dysferlinopathy phenotype.</p> Methods and Results <p>Two affected male siblings underwent comprehensive clinical and biochemical evaluation, lower-limb magnetic resonance imaging (performed in the proband), whole-exome sequencing, Sanger validation, and segregation analysis. A homozygous missense variant in <i>DYSF</i>, c.2998T &gt; C (p.Ser1000Pro), was identified in both affected siblings, with heterozygous carriage confirmed in both parents. This variant has not been assigned a clinical interpretation. Structural modeling revealed localized disruption of the DysF domain of dysferlin, including steric clashes and loss of hydrogen-bond interactions, findings consistent with impaired protein stability and defective membrane repair.</p> Conclusions <p>This study provides the first clinical, structural, and ACMG-based interpretation of the <i>DYSF</i> c.2998T &gt; C (p.Ser1000Pro) variant in Tunisian siblings with LGMD R2, thereby expanding the mutational spectrum of dysferlinopathy.</p>

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Dysferlinopathy due to a homozygous DYSF DysF-domain variant in a non-consanguineous Tunisian family

  • 期刊论文

  • 发表日期：

    2026年2月21日

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  • Ikhlass Belhassen,
  • Pedro M. Rodríguez Cruz,
  • Salma Sakka,
  • Juliette Nectoux,
  • Sawsan Daoued,
  • Chokri Mhiri,
  • France Leturcq,
  • Mariem Dammak

摘要

Background

Dysferlinopathies are autosomal recessive neuromuscular disorders caused by pathogenic variants in the DYSF gene, most commonly presenting as limb-girdle muscular dystrophy type R2 (LGMD R2). In this study, we investigated a non-consanguineous Tunisian family with a classical proximal dysferlinopathy phenotype.

Methods and Results

Two affected male siblings underwent comprehensive clinical and biochemical evaluation, lower-limb magnetic resonance imaging (performed in the proband), whole-exome sequencing, Sanger validation, and segregation analysis. A homozygous missense variant in DYSF, c.2998T > C (p.Ser1000Pro), was identified in both affected siblings, with heterozygous carriage confirmed in both parents. This variant has not been assigned a clinical interpretation. Structural modeling revealed localized disruption of the DysF domain of dysferlin, including steric clashes and loss of hydrogen-bond interactions, findings consistent with impaired protein stability and defective membrane repair.

Conclusions

This study provides the first clinical, structural, and ACMG-based interpretation of the DYSF c.2998T > C (p.Ser1000Pro) variant in Tunisian siblings with LGMD R2, thereby expanding the mutational spectrum of dysferlinopathy.