Clinical, Histological, and Genetic Characterization of a Large Cohort of 49 Patients With Nebulin-Related Congenital Myopathy.

Congenital nemaline myopathies are rare genetic disorders that typically manifest at birth or in childhood, with muscle weakness and respiratory distress. They are characterized by the presence of rod-like structures on the muscle biopsy, or a mix of rods with cores, focal areas with disorganization of oxidative activity. Pathogenic variants in the NEB gene represent a main cause of these conditions. However, significant phenotypic variability exists, hampering disease prognosis, healthcare, and genetic counseling. This study is aimed at further characterizing the clinical and genetic features of nebulin-related congenital myopathies and exploring genotype-phenotype correlations in a novel large cohort of patients. In a total of 49 patients from 48 families with nebulin-related myopathies, a substantial proportion (23/49) exhibited a typical form of the disease, with childhood onset and preserved ambulation beyond 11 years of age. Respiratory insufficiency was observed in 33/49 patients, with a median age of 16 years for the initiation of ventilatory support. Facial muscle weakness was common (32/49), whereas severe bulbar symptoms were less frequent, with only 14/49 requiring nutritional support, all in cases where respiratory assistance was necessary. Patients with rods (n = 28) or core-rods (n = 11) exhibited no significant clinical differences. Genetic analysis identified 76 NEB variants, including 7 recurrent, with a mutational hotspot detected between Exons 169 and 175 in 25/49 patients. Furthermore, our analyses suggest an association between the type of variant and five groups of patients with different levels of clinical severity. Additionally, our data raise the possibility that ophthalmoplegia may be preferentially observed in patients harboring variants located in Exon 143. Overall, these findings will contribute to facilitating and expediting genetic diagnosis in future cases with suspected NEB involvement, ultimately improving patient care and management.