COLLAGEN RELATED MUSCLE DISEASES: EP.59 Genetic etiology of retractile myopathies in a cohort of 80 children under 11 years following NGS analysis

Abstract

The retractile myopathies consist of rare diseases with skeletal muscles and connective tissue damages. They are mostly characterized by progressive muscle weakness, joint contractures and distal hyperlaxity. A rigid spine, dropped head, scoliosis or skin involvement can distinguish some of them. The purpose of this study is the detection of gene causative variants responsible for retractile myopathies in a cohort of 80 pediatric patients sequenced by Next-Generation Sequencing (NGS). This retrospective study includes patients followed between June 2015 until March 2021 in French neuromuscular reference centers. All the referred patients of the cohort were under 11 years old and developed the first symptoms at birth or in early childhood, mostly exhibiting hypotonia for newborn patients or limb girdle myopathy, joint contractures and distal hyperlaxity for children. Genetic testing used targeted NGS panel including 30 genes associated with retractile and hyperlaxity myopathies. Among the 80 analysed patients, 40 could benefit of a disease-causing genetic etiology (50%). Among the 30 genes, 14 genes were involved. The most frequently mutated genes include the group of the COL6 genes (37.5% of patients with COL6A1, COL6A2 and COL6A3) and TTN (17.5% of patients). Interestingly, two patients were mutated in PLOD1 gene, each carrying a homozygous variant. Among the families where heritability could be analysed, eight patients exhibited a de novo dominant variant (20% of the children). In conclusion, the increased accessibility to NGS improves the field of children patients with a genetic diagnosis up to 50%. Furthermore, we confirm the interest of integrating PLOD1 gene into this panel as it was involved in 5% of patients. This allows better orientation of medical care and genetic counseling for these families.