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

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.