Key result
Reanalysis of rare missense TTN variants using ACMG recommendations resulted in the reclassification of 36.8% of variants from unknown significance to benign or likely benign.
Why the study?
Missense TTN variants represent a clinical diagnostic challenge, and many ambiguous variants in inherited arrhythmogenic syndromes were classified before the 2015 ACMG recommendations.
Observational (n=193)
Periodical reclassification of rare missense TTN variants using updated ACMG guidelines significantly alters variant interpretation, reducing ambiguous diagnoses in inherited arrhythmogenic syndromes.
TTN missense variants remain a diagnostic challenge in arrhythmias; leaves open systematic reclassification of pre-2015 variants under current ACMG criteria.
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.
No takes yet. Share an insight, caveat, or question.
Martinez-Barrios et al. (2022) conducted an observational in Inherited arrhythmogenic syndromes (n=193). Reanalysis of rare missense TTN variants using ACMG recommendations vs. Pre-2015 classification was evaluated on Reclassification of missense variants from unknown to benign/likely benign. Reanalysis of rare missense TTN variants using ACMG recommendations resulted in the reclassification of 36.8% of variants from unknown significance to benign or likely benign.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: