Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

Abstract

A B S T R A C TBackground: Accurate interpretation of rare genetic variants is a challenge for clinical translation. Updates in recommendations for rare variant classification require the reanalysis and reclassification. We aim to perform an exhaustive re-analysis of rare variants associated with inherited arrhythmogenic syndromes, which were classified ten years ago, to determine whether their classification aligns with current standards and research findings. Methods: In 2010, the rare variants identified through genetic analysis were classified following recommendations available at that time. Nowadays, the same variants have been reclassified following current American College of Medical Genetics and Genomics recommendations. Findings: Our cohort included 104 cases diagnosed with inherited arrhythmogenic syndromes and 17 postmortem cases in which inherited arrhythmogenic syndromes was cause of death. 71.87% of variants change their classification. While 65.62% of variants were classified as likely pathogenic in 2010, after reanalysis, only 17.96% remain as likely pathogenic. In 2010, 18.75% of variants were classified as uncertain role but nowadays 60.15% of variants are classified of unknown significance. Interpretation: Reclassification occurred in more than 70% of rare variants associated with inherited arrhythmogenic syndromes. Our results support the periodical reclassification and personalized clinical translation of rare variants to improve diagnosis and adjust treatment.

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

“…Likewise, 27% (59/218) of the pLoF variants were downgraded by our manual review of sequence reads. Together, these ClinVar, review, and pLoF variants that were downgraded by our curation (77/463, 17%) had markedly reduced effect sizes compared to variants we curated as clinically significant (Supplementary Data 4) [23][24][25][26] . These findings support our curation process and highlight the need for caution in relying on available variant designations without additional review.…”

“…25 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore. 26 Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore. 27 Duke-NUS Medical School, Singapore, Singapore.…”

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

“…Likewise, 27% (59/218) of the pLoF variants were downgraded by our manual review of sequence reads. Together, these ClinVar, review, and pLoF variants which were downgraded by our curation (77/463, 17%) had marked reduced effect sizes compared to variants we curated as clinically significant (Supplementary Table 5) [24][25][26][27] . These findings support our curation process and highlight the need for caution in relying on available variant designations without additional review.…”

Sudden cardiac death in children and young adults without structural heart disease: a comprehensive review

“…Continued relationship with periodic follow up with the family is recommended as variant reclassification may occur over the course of years as new information becomes available. In a recent study of reinterpretation of sequence variants in genes causing inherited arrhythmogenic syndromes, reanalysis lead to reclassification of 70% of variants classified 10 years prior (Campuzano et al, 2020). Many clinical laboratories offer periodic reclassification, which often requires an ordering clinician to request the reanalysis.…”