VP.03 Diagnosing Titinopathy: lessons from a multi-omics pilot study

Abstract

Titinopathy, or skeletal muscular dystrophy caused by autosomal recessive mutations in Titin (<i>TTN</i>), poses a unique diagnostic challenge because of A) significant variation in clinical manifestation, B) presence of rare putative deleterious <i>TTN</i> variants amongst healthy individuals which increases likelihood of incidental findings. Altogether, this makes establishing a definite diagnosis of Titinopathy based solely on phenotypic and genotypic information virtually impossible in the absence of corroborative evidence. We report six patients with Titinopathy from four unrelated families. In each case, prior genomics-based efforts had failed to reach a conclusive diagnosis and a confirmed diagnosis was reached by co-analyzing patient genomic and transcriptomic data. The multi-omics approach provided direct evidence confirming or dismissing impact of plausible candidate variants in TTN and other genes. This clarity of information was critical in solving these cases. The phenotypic diversity of the cohort highlights the diagnostic challenge. The first family included two siblings presented with adolescent onset multiple joint contractures, slowly progressive spine rigidity and elevated Creatine Kinase (CK). The severity of condition varied amongst the siblings with elder brother exhibited mild limb girdle weakness not seen in the younger sister. The second and third families comprise of a girl and boy respectively. Both unrelated patients had similar symptoms characterized by early onset hypotonia, delayed walking and elevated CK. Both had limb girdle muscle weakness and mild scoliosis. Their motor performance had been stable, and both continued to walk independently in adulthood. The fourth family included two siblings presented with arthrogryposis multiplex congenita and hypotonia after birth. Their mother reported decreased fetal movement during both pregnancies. Both elder sister and younger brother had delayed walking and limb girdle weakness. However, their joint contractures improved with age and regular stretching. The younger brother also had autistic features. Both siblings had normal CK. All patients in the study had normal echocardiogram suggesting lack of cardiac involvement. Our multi-omics findings link individualized patient condition to the specific functional impact of their implicated mutations.