The giant titin: how to evaluate its role in cardiomyopathies

Azad, Amar J.; Poloni, Giulia; Sontayananon, Naeramit; Gehmlich, Katja

doi:10.1007/s10974-019-09518-w

Cited by 11 publications

(14 citation statements)

References 87 publications

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“…Rare genetic alterations in the TTN gene are associated with inherited cardiomyopathies, mainly DCM [10,28]. However, most reported deleterious variants are "radical" (nonsense and indels) [9,29,30], and only a few studies have examined the pathogenicity of missense TTN variants in inherited cardiomyopathies [31][32][33][34][35].…”

Section: Cardiomyopathiesmentioning

confidence: 99%

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes

Martínez-Barrios

Sarquella-Brugada

Pérez-Serra

et al. 2022

JPM

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The titin gene (TTN) is associated with several diseases, including inherited arrhythmias. Most of these diagnoses are attributed to rare TTN variants encoding truncated forms, but missense variants represent a diagnostic challenge for clinical genetics. The proper interpretation of genetic data is critical for translation into the clinical setting. Notably, many TTN variants were classified before 2015, when the American College of Medical Genetics and Genomics (ACMG) published recommendations to accurately classify genetic variants. Our aim was to perform an exhaustive reanalysis of rare missense TTN variants that were classified before 2015, and that have ambiguous roles in inherited arrhythmogenic syndromes. Rare missense TTN variants classified before 2015 were updated following the ACMG recommendations and according to all the currently available data. Our cohort included 193 individuals definitively diagnosed with an inherited arrhythmogenic syndrome before 2015. Our analysis resulted in the reclassification of 36.8% of the missense variants from unknown to benign/likely benign. Of all the remaining variants, currently classified as of unknown significance, 38.3% showed a potential, but not confirmed, deleterious role. Most of these rare missense TTN variants with a suspected deleterious role were identified in patients diagnosed with hypertrophic cardiomyopathy. More than 35% of the rare missense TTN variants previously classified as ambiguous were reclassified as not deleterious, mainly because of improved population frequencies. Despite being inconclusive, almost 40% of the variants showed a potentially deleterious role in inherited arrhythmogenic syndromes. Our results highlight the importance of the periodical reclassification of rare missense TTN variants to improve genetic diagnoses and help increase the accuracy of personalized medicine.

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Section: Cardiomyopathiesmentioning

confidence: 99%

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes

Martínez-Barrios

Sarquella-Brugada

Pérez-Serra

et al. 2022

JPM

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“…Thick filaments are anchored by a structure called the M-band [ 10 ], while thin filament are anchored by the Z-disc [ 11 ]. Titin, the third filament, connects Z-discs and M-bands by spanning half a sarcomere [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

Wadmore

Azad

Gehmlich

2021

IJMS

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The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts.

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“…Titin truncating variants (nonsense, frameshift, essential splice site) underlie 25% of familial cases of idiopathic dilated cardiomyopathy, but truncating variants that affect all transcripts are rare in the general population [ 40 , 41 ]. The majority of dilated cardiomyopathy cases are inherited in an autosomal dominant manner; the exact pathogenesis of titin truncating variants is unknown but a dominant negative mode of action, albeit not through a poisonous-protein mechanism, is thought more likely than haploinsufficiency [ 42 , 43 ].…”

Section: Pharmacogenomics In Clinical Cardiovascular Medicinementioning

confidence: 99%

The Interface of Therapeutics and Genomics in Cardiovascular Medicine

Magavern

Kaski

Turner

et al. 2021

Cardiovasc Drugs Ther

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Pharmacogenomics has a burgeoning role in cardiovascular medicine, from warfarin dosing to antiplatelet choice, with recent developments in sequencing bringing the promise of personalised medicine ever closer to the bedside. Further scientific evidence, real-world clinical trials, and economic modelling are needed to fully realise this potential. Additionally, tools such as polygenic risk scores, and results from Mendelian randomisation analyses, are only in the early stages of clinical translation and merit further investigation. Genetically targeted rational drug design has a strong evidence base and, due to the nature of genetic data, academia, direct-to-consumer companies, healthcare systems, and industry may meet in an unprecedented manner. Data sharing navigation may prove problematic. The present manuscript addresses these issues and concludes a need for further guidance to be provided to prescribers by professional bodies to aid in the consideration of such complexities and guide translation of scientific knowledge to personalised clinical action, thereby striving to improve patient care. Additionally, technologic infrastructure equipped to handle such large complex data must be adapted to pharmacogenomics and made user friendly for prescribers and patients alike.

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The giant titin: how to evaluate its role in cardiomyopathies

Cited by 11 publications

References 87 publications

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

The Interface of Therapeutics and Genomics in Cardiovascular Medicine

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