44P Novel TTN mutation causing a congenital onset, slowly progressive myopathy with contractures in two siblings

• Published in: Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.242
• Main Authors: Bonaparte, S. Figueroa, Martinez-Viguera, A., Juanola-Mayos, E., Lucente, G., Almendrote, M., Gasch-Navalon, E., Corral-Juan, M., Matilla-Dueñas, A., Martinez-Piñeiro, A.
• Format: Article
• Language: English
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.251

Titin-related myopathy is an emerging genetic neuromuscular disorder with a wide spectrum of clinical phenotypes. This report describes a novel TTN-related phenotype in two siblings, both affected by a congenital onset, with very slowly progressive dystrophic myopathy and contractures. Patients were born with generalized hypotonia. They progressively developed a bilateral winged scapula, rigid spine, and a proximal girdle and distal weakness in both hands and feet. Muscle magnetic resonance imaging revealed severe involvement of paraspinal muscles, gluteal, anterior and posterior thigh, as well as both gastrocnemius muscles. Clinical exome sequencing in both siblings identified in compound heterozygosity the probably pathogenic variant c.35756del (p.Pro11919LeufsTer51) in exon 162 and the probably pathogenic variant c.79663G>T (p.Glu26555Ter) in exon 326 of the TTN gene, a gene previously associated with loss of function variants and dilated cardiomyopathy. The c.35756del generates a frameshift and a premature stop codon, being reported in the ClinVar database as of uncertain significance revealing a frequency of 0.002% (gnomAD-Genomes). The novel variant c.79663G>T also generates a premature stop codon in the TTN gene and is not currently reported in any database. Since the asymptomatic father is a c.79663G>T (exon 326) carrier, both pathogenic variants in the sibling may trigger loss of titin protein function. We report here two cases with congenital onset slowly progressive myopathy with contractures due to two, one novel, loss-of-function variants within the TTN gene expanding the clinical phenotype.