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Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population
Mathieu Cerino1, Patricio González-Hormazábal2, Mario Abaji1
1Marseille Medical Genetics Université, INSERM, U 1251, Aix-Marseille Université, 13005 Marseille, France.
Insights
Genetic testing identified the causes of hereditary myopathies in over 69% of Chilean patients with limb-girdle muscle weakness. Dysferlinopathy and calpainopathy were the most common genetic forms identified.
Area of Science:
- Neuromuscular Disorders
- Clinical Genetics
- Molecular Biology
Background:
- Hereditary myopathies encompass over 300 genetic muscle disorders.
- Chile lacks specific registries for these distinct myopathies.
- Limb-girdle muscle weakness is a common presentation of unknown etiology.
Purpose of the Study:
- To investigate the genetic underpinnings of hereditary myopathies in Chilean patients.
- To establish a genetic diagnosis for individuals with limb-girdle muscle weakness of unknown cause.
Main Methods:
- High-throughput sequencing utilizing neuromuscular gene panels.
- Analysis of 82 patients presenting with limb-girdle muscle weakness.
Main Results:
- A definitive genetic diagnosis was achieved in 59.8% of patients, with a probable diagnosis in an additional 9.8%.
- The most frequent causative genes were *DYSF* (22%) and *CAPN3* (8.5%), followed by *DMD* and *RYR1* (4.9% each).
- Twelve novel variants were identified, and 6.1% of patients had variants of uncertain significance; 24.4% had no pathogenic variants in related genes, including 5 with autoimmune disorders.
Conclusions:
- High-throughput sequencing is effective for diagnosing hereditary myopathies in Chile.
- The genetic landscape of myopathies in Chile appears similar to global data, with a potential higher incidence of dysferlinopathy.
- Further research is needed for patients without a clear genetic diagnosis, including autoimmune conditions.
Abstract:
Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with limb-girdle muscle weakness of unknown etiology. Eighty-two patients were explored using high-throughput sequencing approaches with neuromuscular gene panels, establishing a definite genetic diagnosis in 49 patients (59.8%) and a highly probable genetic diagnosis in eight additional cases (9.8%). The most frequent causative genes identified were DYSF and CAPN3, accounting for 22% and 8.5% of the cases, respectively, followed by DMD (4.9%) and RYR1 (4.9%). The remaining 17 causative genes were present in one or two cases only. Twelve novel variants were identified. Five patients (6.1%) carried a variant of uncertain significance in genes partially matching the clinical phenotype. Twenty patients (24.4%) did not carry a pathogenic or likely pathogenic variant in the phenotypically related genes, including five patients (6.1%) presenting an autoimmune neuromuscular disorder. The relative frequency of the different forms of myopathy in Chile is like that of other series reported from different regions of the world with perhaps a relatively higher incidence of dysferlinopathy.
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