New TTN Gene Variants Potentially Linked to Limb-girdle MD, Study Says

Limb-girdle muscular dystrophy (LGMD) may be caused by previously unidentified TTNgene variants that are also associated with heart muscle disease, according to a study.

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 dystrophyhereditary 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.

Source : MD News

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Public Health to us at MDCRC is about the community at large. The health of the community at different levels and when seen through different perspectives becomes a subject which is complete, holistic and is a melting pot for a plethora of technical disciplines. At MDCRC we do align with a goal of working for community health by working on modular projects related to Women and Child health, disease prevention, Health informatics, Community building and its associated research, Water resources, Arts, Indic Sciences, Cultural issues which are relevant to the contemporary generation. The style which we adopt is to focus on totally neglected aspects and form a working model towards a better situation. The need for this approach is to bring back the glory of humanity in general and which percolates to a healthier India.

The disorders in current focus are Orphan disorders, meaning disorders whose numbers are said to be less (in the Western diaspora) which neither doesn’t majorly impact the community’s currently used health metric nor does it provide a base for extensive drug research and its production. This view is only true until the numbers are low and also the way we look at Public health in general. There had been no concerted efforts in the domain of Orphan disorders in India. Mission of ours then, was to bring the science, the services pertaining to a particular problem statement and which thereby gives rise to an evolution of a model. This forges a way of approaching Health from a community standpoint thereby offering an impactful experience to all stake-holders. This is where the core culture MDCRC comes in where we believe that in Public Health domain in particular, the science and the associated services need to reach mankind at large without a number bias or number crunching.

With a background in Biochemistry and Genetics, Dr. Lakshmi, in 2006 had started working on genetic disorders with specific emphasis on community building.

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