Abstract
ObjectiveComprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.MethodsUsing massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients.ResultsAll patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap‐like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near‐normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One‐third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder.InterpretationThis detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105–1124
Highlights
Direct analysis of the impact of each mutation was beyond the scope of this study; an in vitro hybrid minigene splicing assay was previously used to evaluate the transcriptional consequences of 2 splice site changes.[22]
Since massively parallel sequencing (MPS) “opened the door” to the comprehensive genetic analysis of TTN, congenital titinopathy has emerged as an important cause of early onset myopathy
Using MPS, we identified an international cohort of 30 individuals with early onset muscle weakness and/or contractures, and recessively inherited nonsense, frameshift, and/or splice site TTN mutations
Summary
Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. Has the longest coding sequence (>100kb) of any human gene It encodes titin, the largest protein in nature (maximum size 5 4,200kDa).[1] In striated (cardiac and skeletal) muscle, each titin molecule pairs with a second antiparallel titin molecule to span the full length of the sarcomere like two “springs in series,”[2] forming a continuous elastic myofilament. To facilitate diagnostic assessments and to better understand the natural history of congenital titinopathy, we analyzed the clinical, muscle pathology and imaging findings in a large international cohort with recessively inherited nonsense, frameshift and/or splice site TTN mutations; that is, the most pathogenically-convincing subset of mutations. Patients with difficult-to-interpret missense variants were excluded, to gain the clearest possible clinical picture of this disorder
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