Multi-omics approach identifies a novel recessive pathogenic variant in the TNNT3 gene in two siblings with congenital myopathy

Juliane S Müller; Shira Rabinowicz; Irina Zaharieva; Veronica Pini; Vicente A Yépez; Anna Esteve-Codina; Darren Chambers; Andrew Dawson; Luke Perry; Brian Herron; Estelle Healy; Sandya Tirupathi; Ana Töpf; Stephanie DiTroia; Rahul Phadke; Francesco Muntoni; Anna Sarkozy

doi:10.1016/j.nmd.2025.105415

Multi-omics approach identifies a novel recessive pathogenic variant in the TNNT3 gene in two siblings with congenital myopathy

Neuromuscul Disord. 2025 Jun 3:52:105415. doi: 10.1016/j.nmd.2025.105415. Online ahead of print.

Authors

Juliane S Müller¹, Shira Rabinowicz², Irina Zaharieva², Veronica Pini², Vicente A Yépez³, Anna Esteve-Codina⁴, Darren Chambers², Andrew Dawson⁵, Luke Perry², Brian Herron⁶, Estelle Healy⁶, Sandya Tirupathi⁷, Ana Töpf⁸, Stephanie DiTroia⁹, Rahul Phadke², Francesco Muntoni², Anna Sarkozy²

Affiliations

¹ The Dubowitz Neuromuscular Centre, University College London, Great Ormond Street, Institute of Child Health and MRC Centre for Neuromuscular Diseases, Neurosciences Unit, Great Ormond Street Hospital, London, UK. Electronic address: j.mueller@ucl.ac.uk.
² The Dubowitz Neuromuscular Centre, University College London, Great Ormond Street, Institute of Child Health and MRC Centre for Neuromuscular Diseases, Neurosciences Unit, Great Ormond Street Hospital, London, UK.
³ School of Computation, Information and Technology, Technical University of Munich, Garching bei München, Germany.
⁴ Centre Nacional d'Anàlisi Genòmica (CNAG), Baldiri Reixac 4, Barcelona, 08028, Spain and Universitat de Barcelona (UB), Barcelona, Spain.
⁵ Department of Neuropathology, University College London Hospital, London, UK.
⁶ Department of Neuropathology, Royal Victoria Hospital, Belfast, UK.
⁷ Department of Paediatric Neurology, Royal Belfast Hospital for Sick Children, Belfast, UK.
⁸ John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁹ Program in Medical and Population Genetics, Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

PMID: 40554860
DOI: 10.1016/j.nmd.2025.105415

Abstract

TNNT3 is the fast skeletal muscle troponin T compound of the troponin complex. Dominantly inherited pathogenic missense variants in TNNT3 cause distal arthrogryposis, whereas rare recessive TNNT3 variants are associated with congenital myopathy with distal arthrogryposis with and without nemaline rods. Here, we report two teenage sisters who presented at birth with hypotonia, proximal weakness, feeding difficulties and finger contractures. Muscle weakness was not progressive and clinical function improved over time. Muscle biopsies showed small atrophic fast fibres, internal nuclei, increased connective tissue and focal fat infiltration. Ultrastructural investigation revealed disorganised myofibrils and nemaline bodies in some fibres. Targeted sequencing of panel of genes causing congenital myopathy was negative. Trio whole exome and genome sequencing identified a novel homozygous intronic TNNT3 variant, c.67+128G>A. Sequencing of RNA derived from the patient's muscle confirmed the variant's detrimental effect on splicing. This work expands the allelic spectrum of TNNT3 related congenital myopathy and confirms the previously reported favourable disease course in some patients, although with an overall milder disease presentation in both siblings. It also highlights the utility of a combined multi-omics approach to diagnose previously unsolved cases of congenital myopathy.

Keywords: Congenital myopathy; Nemaline bodies; RNA sequencing; TNNT3; Troponin T.