Findings of the study, “Investigation of TTN variants in patients with Limb-Girdle Muscular Dystrophy identifies novel Titinopathies,” were presented by Kelly Rich at the 2019 American Academy of Neurology (AAN) annual meeting, taking place through May 10 in Philadelphia.
Variants in the TTN gene are associated with different skeletal myopathies (muscle diseases), namely tibial muscular dystrophy, hereditary myopathy with early respiratory failure, and also LGMD (2J subtype).
Only one variant is known to cause LGMD2J, and these differences are frequently considered incidental and/or of uncertain clinical significance (VUS).
VUS are considered a common complication of next-generation sequencing (NGS), a technique of extreme importance for diagnostics, making the interpretation of results not always straightforward.
The research team at The Ohio State University Wexner Medical Center intended to review, classify, and assess the clinical significance of TTN variants in LGMD patients who underwent NGS in a tertiary care clinic.
Variants classified as pathogenic, likely pathogenic, or VUS were evaluated, while those regarded as potentially causative of LGMD were investigated via an approach called segregation analysis and family studies.
Genetic analysis identified 20 patients with one or more TTN gene variants. In particular, five patients (25%) showed missense variants — changes in the building blocks of DNA, called nucleotides, leading to a different amino acid — which were classified as VUS and not investigated further.
Two patients (10%) had pathogenic TTN missense variants associated with hereditary myopathy with early respiratory failure. The other 13 patients (65%) had different variants, including truncating mutations — DNA changes that can shorten the resulting protein — and deletions (loss of nucleotides during DNA replication), which were classified as VUS or likely pathogenic for cardiac disease.
In four cases (20%), truncating or deletion variants affecting the A-band of the titin protein — generated from the TTN gene and whose alterations cause titinopathies — correlated with LGMD and dilated cardiomyopathy (DCM), a heart condition. According to the team, this suggests that these gene changes may cause autosomal dominant LGMD with DCM. Autosomal dominant conditions are those where a mutation in one of the two gene copies is sufficient to trigger disease-related alterations.
Overall, “the clinical spectrum of titinopathies may be broader than previously recognized and pathogenic variants in TTN may account for a portion of the 60% of LGMD cases which are currently genetically uncharacterized,” the scientists wrote.
As such, TTN should be considered in the “differential diagnosis of any patient with a personal or family history skeletal myopathy and cardiomyopathy,” the poster read.
Moreover, Rich highlighted the importance of multidisciplinary care, as cross-referrals between neurology and cardiology allowed the identification of these cases.