PT - JOURNAL ARTICLE AU - Justine Géraud AU - Klaus Dieterich AU - John Rendu AU - Emmanuelle Uro Coste AU - Murielle Dobrzynski AU - Pascale Marcorelle AU - Christine Ioos AU - Norma Beatriz Romero AU - Eloise Baudou AU - Julie Brocard AU - Anne-Cécile Coville AU - Julien Fauré AU - Michel Koenig AU - Raul Juntas Morales AU - Emmanuelle Lacène AU - Angéline Madelaine AU - Isabelle Marty AU - Henri Pegeot AU - Corinne Theze AU - Aurore Siegfried AU - Mireille Cossee AU - Claude Cances TI - Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy AID - 10.1136/jmedgenet-2019-106714 DP - 2021 Sep 01 TA - Journal of Medical Genetics PG - 602--608 VI - 58 IP - 9 4099 - http://jmg.bmj.com/content/58/9/602.short 4100 - http://jmg.bmj.com/content/58/9/602.full SO - J Med Genet2021 Sep 01; 58 AB - Background Congenital nemaline myopathies are rare pathologies characterised by muscle weakness and rod-shaped inclusions in the muscle fibres.Methods Using next-generation sequencing, we identified three patients with pathogenic variants in the Troponin T type 1 (TNNT1) gene, coding for the troponin T (TNT) skeletal muscle isoform.Results The clinical phenotype was similar in all patients, associating hypotonia, orthopaedic deformities and progressive chronic respiratory failure, leading to early death. The anatomopathological phenotype was characterised by a disproportion in the muscle fibre size, endomysial fibrosis and nemaline rods. Molecular analyses of TNNT1 revealed a homozygous deletion of exons 8 and 9 in patient 1; a heterozygous nonsense mutation in exon 9 and retention of part of intron 4 in muscle transcripts in patient 2; and a homozygous, very early nonsense mutation in patient 3.Western blot analyses confirmed the absence of the TNT protein resulting from these mutations.Discussion The clinical and anatomopathological presentations of our patients reinforce the homogeneous character of the phenotype associated with recessive TNNT1 mutations. Previous studies revealed an impact of recessive variants on the tropomyosin-binding affinity of TNT. We report in our patients a complete loss of TNT protein due to open reading frame disruption or to post-translational degradation of TNT.All data relevant to the study are included in the article or uploaded as supplementary information.