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.

Exon skipping is a promising therapeutic approach. One important condition for this approach is that the exon-skipped form of the gene can at least partially perform the required function and lead to improvement of the phenotype. It is therefore critical to identify the exons that can be skipped without a significant deleterious effect on the protein function. Pathogenic variants in the DMD gene are responsible for Duchenne muscular dystrophy (DMD). We report for the first time a deletion of the in-frame exon 49 associated with a strikingly normal muscular phenotype. Based on this observation, and on previously known therapeutic approaches using exon skipping in DMD for other single exons, we aimed to extend the clinical use of exon skipping for patients carrying truncating mutations in exon 49. We first determined the precise genomic position of the exon 49 deletion in our patients. We then demonstrated the feasibility of skipping exon 49 using an in vitro AON (antisense oligonucleotide) approach in human myotubes carrying a truncating pathogenic variant as well as in healthy ones. This work is a proof of concept aiming to expand exon-skipping approaches for DMD exon 49.

The TRAPP (TRAfficking Protein Particle) complexes are evolutionarily conserved tethering factors involved in the intracellular transport of vesicles for secretion and autophagy processes. Pathogenic variants in 8 genes (of 14) encoding TRAPP proteins are involved in ultra-rare human diseases, called TRAPPopathies. Seven of them are autosomal recessive neurodevelopmental disorders with overlapping phenotypes. Since 2018, two homozygous missense variants inTRAPPC2Lhave been reported in five individuals from three unrelated families with early-onset and progressive encephalopathy, with episodic rhabdomyolysis. We now describe the first pathogenic protein-truncating variant in theTRAPPC2Lgene found at a homozygous state in two affected siblings. This report provides key genetic evidence invaluable to establishing the gene-disease relationship for this gene and important insights into the TRAPPC2L phenotype. Regression, seizures and postnatal microcephaly initially described are not constant features. Acute episodes of infection do not contribute to the neurological course. HyperCKaemia is part of the clinical picture. Thus, TRAPPC2L syndrome is mainly characterised by a severe neurodevelopmental disorder and a variable degree of muscle involvement, suggesting that it belongs to the clinical entity of rare congenital muscular dystrophies.

Hutchinson‐Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic disorder characterized by accelerated aging. The accumulation of an abnormal and toxic protein called progerin within HGPS nuclei disrupts cellular processes, including gene expression and DNA repair. Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defense, is one of the hallmarks of HGPS. To identify novel molecular mechanisms underlying HGPS pathogenesis, we performed miRNA expression profiling in HGPS compared to healthy control fibroblasts. We identified 10 differentially expressed (DE) miRNAs between HGPS and control cells. We focused on miR‐140‐5p and miR‐140‐3p, 2 miRNAs upregulated in HGPS fibroblasts. miR‐140‐5p is known to directly target the transcript of NRF2 , a master regulator of the antioxidant response. Using in vitro mimic and antimiR transfections, we demonstrated that miR‐140‐5p overexpression in HGPS fibroblasts results in the downregulation of the NRF2/KEAP1/HO‐1 antioxidant pathway, leading to increased oxidative stress. Furthermore, our results indicate that miR‐140‐5p overexpression induces mitochondrial dysfunction, characterized by a reduced oxidative phosphorylation capacity and affects other hallmarks of aging. By targeting regulation of oxidative stress and mitochondrial function through NRF2, miR‐140‐5p may play a pivotal role in the pathophysiology of HGPS and open new therapeutic avenues.

Summary: What is already known about this topic? What does this study add?