CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.235Recessive congenital fiber type disproportion caused by TPM3 mutation

Abstract

Mutations in TPM3 gene represent a common cause of congenital fiber type disproportion (CFTD), but can also lead to other phenotypes like nemaline myopathy, cap myopathy, and congenital muscle stiffness. The clinical severity is also highly variable and genotype/phenotype correlations have been inconsistent. The majority of previously reported TPM3-associated diseases are dominantly acting, either inherited or de novo. Recessive cases are very rare and previously related to severe forms of recessive nemaline myopathy and one severely affected patient with CFTD. Here we present an autosomal recessive CFTD case harboring a novel homozygous mutation in TPM3 presenting with a mild proximal phenotype. Case Report: a 14-year-old female, only child of consanguineous parents. She was born hypotonic followed by delayed acquisition of motor milestones. Head support was achieved at the age of 6 months and gait at 30 months. At the time of the evaluation, she could walk for more than 1000 meters, climb stairs without support, but could never jump. The physical exam showed facial weakness, mild ptosis but no ophtalmoparesis and mild thoracic deformity. She presented a mild proximal cervical weakness combined with a moderate involvement of cervical flexors and no distal weakness. Muscle biopsy of the biceps brachii performed at the age of 4 years showed fiber type disproportion with type 1 predominance and smallness without other structural features like rods, nuclear centralization or cores. Whole exome sequencing revealed a novel homozygous missense variant (p.R179G) in exon 5 of TPM3 gene. The variant is not present in the population databases (EXAC, GNoMED, EVS), it is located in a very conserved residue and is predicted to be damaging according MetaSVM and MetaLR. Herein we presented a novel homozygous variant in TPM3 gene causing a mild CFTD expanding the phenotype-genotype correlations related to this gene and also adding a new variant associated with muscle disease.