Pathogenic variants in encoding the largest human protein, are known to cause dilated cardiomyopathy and several forms of skeletal myopathy. The clinical interpretation of variants is challenging, however, due t
The I-band region of titin displays extensive alternative splicing, generating diverse isoforms that confer tissue-specific mechanical properties in cardiac and skeletal muscles. Through alternative splicing mechanisms, a spectrum of isoforms emerges, tailoring titin's mechanical functions to meet the needs...
Pathogenic variants in TTN were reported to cause a range of skeletal muscle and cardiac disorders, such as dilated cardiomyopathy-1G (CMD1G; OMIM: 604,145), familial hypertrophic cardiomyopathy-9 (CMH9; OMIM: 613,765), tibial muscular dystrophy (TMD; OMIM: 600,334), myofibrillar myopathy-9...
The N2A isoform of TTN is predominantly present in the skeletal muscles, and this N2A isoform excludes some of the exons of predominant cardiac isoforms N2B and N2BA. That is why, mutations of TTN can result in isolated cardiomyopathies, isolated skeletal muscle disor- de...
Depending on the exons involved, age at onset, pattern of muscular involvement and severity may vary.On the other hand, patients with the same missense variant in compound heterozygosity with a TTN tv in a constitutively expressed exon (PSI > 85-90% in pre and postnatal skeletal muscles) ...
Exons not or partially included in any of the cardiac and skeletal muscle main isoforms are defined as “metatranscript-only exons” (MTT-only exons). The effect of a potentially pathogenic variant could have different consequences, whether it is in an MTT-only exon or in a constitutively ...