P.02 Mild nemaline myopathy 10 caused by a novel missense homozygous mutation in LMOD3: broadening the phenotype-genotype correlation

Nemaline myopathy (NM) is a heterogeneous group of conditions characterized by the presence of muscle weakness and the accumulation of nemaline bodies in the muscle biopsy. So far, mutations in 14 genes have been related to both recessive and dominant forms of NM. LMOD3 encodes for the Leimodin-3 protein, which is expressed in the skeletal and cardiac muscle. The majority of described mutations in LMOD3 are truncating mutations and cause a severe autosomal recessive congenital myopathy (NEM-10), characterized by early-onset hypotonia, generalized muscle weakness and respiratory insufficiency. Most of the patients also present polyhydramnios, reduced fetal movements, arthrogryposis or frequent contractures, and they usually die during early childhood. Here we describe a family with two affected adult sisters with a novel homozygous missense mutation in LMOD3 presenting a very mild phenotype, providing further evidence to the phenotype-genotype correlation of NEM-10. The proband, a 54-year-old woman was the first child of healthy consanguineous parents. She presented with mild hypotonia at birth and delayed motor milestones. She was never able to run, and presented frequent falls during infancy. Examination revealed high arched palate, bilateral facial weakness, and mild weakness involving neck flexors, iliopsoas and knee flexors. Her sister had the same phenotype. Serum CK were within normal levels. A muscle biopsy taken from the triceps brachii revealed mild variation in the fiber size, and very rare fibres containing nemaline bodies. Both affected sisters presented a novel homozygous missense c.1030C>T, p.Arg344Trp (NM_198271.4) mutation identified in the LMOD3 gene through a NGS custom gene panel analyzing 139 neuromuscular-related genes. Our work broadens the mutational spectrum of LMOD3 gene and contributes to better understand the clinical heterogeneity of nemaline myopathy. Nemaline myopathy (NM) is a heterogeneous group of conditions characterized by the presence of muscle weakness and the accumulation of nemaline bodies in the muscle biopsy. So far, mutations in 14 genes have been related to both recessive and dominant forms of NM. LMOD3 encodes for the Leimodin-3 protein, which is expressed in the skeletal and cardiac muscle. The majority of described mutations in LMOD3 are truncating mutations and cause a severe autosomal recessive congenital myopathy (NEM-10), characterized by early-onset hypotonia, generalized muscle weakness and respiratory insufficiency. Most of the patients also present polyhydramnios, reduced fetal movements, arthrogryposis or frequent contractures, and they usually die during early childhood. Here we describe a family with two affected adult sisters with a novel homozygous missense mutation in LMOD3 presenting a very mild phenotype, providing further evidence to the phenotype-genotype correlation of NEM-10. The proband, a 54-year-old woman was the first child of healthy consanguineous parents. She presented with mild hypotonia at birth and delayed motor milestones. She was never able to run, and presented frequent falls during infancy. Examination revealed high arched palate, bilateral facial weakness, and mild weakness involving neck flexors, iliopsoas and knee flexors. Her sister had the same phenotype. Serum CK were within normal levels. A muscle biopsy taken from the triceps brachii revealed mild variation in the fiber size, and very rare fibres containing nemaline bodies. Both affected sisters presented a novel homozygous missense c.1030C>T, p.Arg344Trp (NM_198271.4) mutation identified in the LMOD3 gene through a NGS custom gene panel analyzing 139 neuromuscular-related genes. Our work broadens the mutational spectrum of LMOD3 gene and contributes to better understand the clinical heterogeneity of nemaline myopathy.