Diagnosing Titinopathy: lessons from a multi-omics pilot study in Hong Kong

Abstract

Background: Titinopathy, or skeletal muscular dystrophy caused by autosomal recessive mutations in Titin (TTN) poses a unique diagnostic challenge due to significant variation in disease symptomatology and presence of confounding rare potentially deleterious TTN variants amongst healthy individuals. This makes establishing causative link between phenotypic and genotypic information virtually impossible in the absence of corroborative evidence. Result : We report six patients with Titinopathy from four unrelated families. In each case the confirmed diagnosis was reached by phenotypic evaluation and co-analyzing patient genomic and transcriptomic data. This provided direct evidence confirming or dismissing any functional impact of observed genetic variants. The phenotypic diversity of the cohort is noted to highlight the diagnostic challenge. The 1st family (Family A) included two siblings presented with childhood onset multiple joint contractures, slowly progressive spine rigidity and elevated Creatine Kinase (CK). The elder brother also has mild limb girdle weakness but not the younger sister. The 2nd family (Family B) included two siblings presented with arthrogryposis multiplex congenita and hypotonia after birth. Mother reported decreased fetal movement during pregnancies. Both elder sister and younger brother had delayed walking and limb girdle weakness. However, their joint contractures improved as they grew older with regular stretching. The younger brother also had mild autistic features. Both siblings had normal CK. The boy from the 3rd family (Family C) and the girl from the 4th family (Family D) had 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. All patients in this study had normal echocardiogram. Five patients had abnormal muscle biopsy findings with either non-specific dystrophic or myopathic changes. Our multi-omics approach link individualized specificity of the patient presentation to the specific transcriptomic impact of the observed mutations.