02P Exploring genotype-phenotype correlations in NEB-related Myopathies.

Autosomal recessive mutations in NEB cause a congenital myopathy typically with nemaline bodies, but the genotype-phenotype correlation in NEB -RM is not well understood. To investigate the genotype-phenotype relationships and clinicopathological characteristics in NEB -RM. We reviewed our database from congenital myopathy patients with two or more NEB variants and analyzed their clinicopathological features. We identified 85 patients with NEB -RM. We found two predominant variants: 31 patients had c.21522+3A>G and 35 had c.24684G>C. Importantly, none were homozygous or compound heterozygous for these variants. All patients with either variant also had additional truncating mutations. Notably, a healthy individual was found to be homozygous for c.24684G>C, suggesting these mutations might be mildly pathogenic. Therefore, we categorized 85 NEB -RM patients into three groups based on their genetic profiles: Group 1 with c.21522+3A>G (31 patients), Group 2 with c.24684G>C (35 patients), and Group 3 with two truncating mutations (19 patients). Group 1 and 2 typically developed symptoms after 1 year (27/31 and 27/35, respectively), whereas Group 3 presented with early-onset disease (<1 year in 15/19, p<0.0001). Respiratory involvements were more common in Group 2 (53% vs. 13% in Group 1, p=0.004), and facial muscle weakness was more prominent in Group 1 (68% vs. 31% in Group 2, p=0.01). Pathologically, nemaline bodies were less frequent in Group 1 (<25% in 7/15 patients, p=0.02) but were abundant in Group 3 (>75% in 6/11, p=0.06). Additionally, nemaline bodies are often scattered in muscle fibers in Group 1 (12/15, p=0.008) while they were often clustered at subsarcolemmal region in Group 2 (9/13, p=0.008). This study is the first to show genotype-phenotype correlations in NEB -RM, identifying two mildly pathogenic variants in Japanese patients with distinct clinicopathological features. [ABSTRACT FROM AUTHOR]