Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy

Geraud, J; Dieterich, Klaus; Rendu, John; Coste, Emmanuelle Uro; Dobrzynski, M; Marcorelle, Pascale; Ioos, Christine; Romero, Norma B.; Baudou, E.; Brocard, Julie; Coville, Anne-Cécile; Fauré, Julien; Kœnig, M.; Morales, Raúl Juntas; Lacène, Emmanuelle; Madelaine, A.; Marty, Isabelle; Pegeot, Henri; Thèze, C.; Siegfried, Aurore; Cossée, Mireille; Cancés, Claude

doi:10.1136/jmedgenet-2019-106714

Cited by 11 publications

(12 citation statements)

References 20 publications

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“…[1][2][3] TNNT1, the TNNT3 paralog encoding slow skeletal muscle troponin T, is responsible for nemaline myopathy 5, Amish type (NEM5; MIM #605355). [16][17][18] First described in consanguineous Amish families in which a homozygous nonsense variant in exon 11 of TNNT1 segregated with disease, NEM5 has subsequently been reported in multiple ethnic groups (Dutch, Hispanic, Palestinians, Ashkenazi, and French) due to other biallelic TNNT1 variants (e.g., exonic deletions, other nonsense variants, and splice variants). 15 NEM5 has neonatal onset and a progressive, fatal course with muscle weakness and atrophy, contractures, and chest wall rigidity causing pectus carinatum.…”

Section: Discussionmentioning

confidence: 99%

Biallelic Pathogenic Variants in TNNT3 Associated With Congenital Myopathy

et al. 2021

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ObjectivePathogenic variants in TNNT3, the gene encoding fast skeletal muscle troponin T, were first described in autosomal dominant distal arthrogryposis type 2B2. Recently, a homozygous splice site variant, c.681+1G>A, was identified in a patient with nemaline myopathy and distal arthrogryposis. Here, we describe the second individual with congenital myopathy associated with biallelic TNNT3 variants.MethodsClinical exome sequencing data from a patient with molecularly undiagnosed congenital myopathy underwent research reanalysis. Clinical and histopathologic data were collected and compared with the single reported patient with TNNT3-related congenital myopathy.ResultsA homozygous TNNT3 variant, c.481-1G>A, was identified. This variant alters a consensus splice acceptor and is predicted to affect splicing by multiple in silico prediction tools. Both the patient reported here and the previously published patient exhibited limb, bulbar, and respiratory muscle weakness from birth, which improved over time. Other shared features include history of polyhydramnios, hypotonia, scoliosis, and high-arched palate. Distal arthrogryposis and nemaline rods, findings reported in the first patient with TNNT3-related congenital myopathy, were not observed in the patient reported here.ConclusionsThis report provides further evidence for the association of biallelic TNNT3 variants with severe recessive congenital myopathy with or without nemaline rods and distal arthrogryposis. TNNT3 sequencing and copy number analysis should be incorporated into the workup of congenital myopathies.

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Section: Discussionmentioning

confidence: 99%

Biallelic Pathogenic Variants in TNNT3 Associated With Congenital Myopathy

et al. 2021

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“…The symptoms of Pt 9 were much milder than that of Amish patients. In addition, most of the reported TNNT1 variations were homozygous null variations [ 36 ], whereas one paternal frameshift variation (c.353delC; p. Thr118MetfsTer16) and one maternal missense variation (c.1A > G; p. Met1Val) were identified in our patients, which expanded the genotype of TNNT1 .…”

Section: Discussionmentioning

confidence: 60%

Clinical and genetic features of infancy-onset congenital myopathies from a Chinese paediatric centre

et al. 2022

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Background Congenital myopathies are a group of rare neuromuscular diseases characterized by specific histopathological features. The relationship between the pathologies and the genetic causes is complex, and the prevalence of myopathy-causing genes varies among patients from different ethnic groups. The aim of the present study was to characterize congenital myopathies with infancy onset among patients registered at our institution. Method This retrospective study enrolled 56 patients based on the pathological and/or genetic diagnosis. Clinical, histopathological and genetic features of the patients were analysed with long-term follow-up. Results Twenty-six out of 43 patients who received next-generation sequencing had genetic confirmation, and RYR1 variations (12/26) were the most prevalent. Eighteen novel variations were identified in 6 disease-causing genes, including RYR1, NEB, TTN, TNNT1, DNM2 and ACTA1. Nemaline myopathy (17/55) was the most common histopathology. The onset ages ranged from birth to 1 year. Thirty-one patients were followed for 3.83 ± 3.05 years (ranging from 3 months to 11 years). No patient died before 1 year. Two patients died at 5 years and 8 years respectively. The motor abilities were stable or improved in 23 patients and deteriorated in 6 patients. Ten (10/31) patients developed respiratory involvement, and 9 patients (9/31) had mildly abnormal electrocardiograms and/or echocardiograms. Conclusion The severity of congenital myopathies in the neonatal/infantile period may vary in patients from different ethnic groups. More concern should be given to cardiac monitoring in patients with congenital myopathies even in those with static courses.

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“…Patient I401 had a homozygous deletion in the TNNT1 gene (c.192+244_388-1191del), predicted to lead to the in-frame deletion of exons 8 and 9. Western blot analysis revealed the total absence of the troponin protein, no smaller band corresponding to the truncated protein was visible [30]. She had a severe phenotype (marked neonatal hypotonia, rods in the muscle biopsy) that was reminiscent of the previously reported patients with recessive pathogenic variants in TNNT1 [30,31].…”

Section: Recently Identified Phenotype-genotype Associationsmentioning

confidence: 69%

“…Western blot analysis revealed the total absence of the troponin protein, no smaller band corresponding to the truncated protein was visible [30]. She had a severe phenotype (marked neonatal hypotonia, rods in the muscle biopsy) that was reminiscent of the previously reported patients with recessive pathogenic variants in TNNT1 [30,31]. The second patient (I172) had a milder phenotype with proximal and axial weakness in childhood.…”

Section: Recently Identified Phenotype-genotype Associationsmentioning

confidence: 72%

An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families

Morales

Perrin

Solé

et al. 2021

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Diagnosis of myopathies is challenged by the high genetic heterogeneity and clinical overlap of the various etiologies. We previously reported a Next-Generation Sequencing strategy to identify genetic etiology in patients with undiagnosed Limb-Girdle Muscular Dystrophies, Congenital Myopathies, Congenital Muscular Dystrophies, Distal Myopathies, Myofibrillar Myopathies, and hyperCKemia or effort intolerance, using a large gene panel including genes classically associated with other entry diagnostic categories. In this study, we report the comprehensive clinical-biological strategy used to interpret NGS data in a cohort of 156 pediatric and adult patients, that included Copy Number Variants search, variants filtering and interpretation according to ACMG guidelines, segregation studies, deep phenotyping of patients and relatives, transcripts and protein studies, and multidisciplinary meetings. Genetic etiology was identified in 74 patients, a diagnostic yield (47.4%) similar to previous studies. We identified 18 patients (10%) with causative variants in different genes (ACTA1, RYR1, NEB, TTN, TRIP4, CACNA1S, FLNC, TNNT1, and PAPBN1) that resulted in milder and/or atypical phenotypes, with high intrafamilial variability in some cases. Mild phenotypes could mostly be explained by a less deleterious effect of variants on the protein. Detection of inter-individual variability and atypical phenotype-genotype associations is essential for precision medicine, patient care, and to progress in the understanding of the molecular mechanisms of myopathies.

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Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy

Cited by 11 publications

References 20 publications

Biallelic Pathogenic Variants in TNNT3 Associated With Congenital Myopathy

Biallelic Pathogenic Variants in TNNT3 Associated With Congenital Myopathy

Clinical and genetic features of infancy-onset congenital myopathies from a Chinese paediatric centre

An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families

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