Reclassification of genetic variants in children with long QT syndrome

Abstract

Background Genes encoding cardiac ion channels or regulating proteins have been associated with the inherited form of long QT syndrome (LQTS). Complex pathophysiology and missing functional studies, however, often bedevil variant interpretation and classification. We aimed to evaluate the rate of change in variant classification based on current interpretation standards and dependent on clinical findings. Methods Medical charts of children with a molecular genetic diagnosis of LQTS presenting at our centers were retrospectively reviewed. Reinterpretation of originally reported variants in genes associated with LQTS was performed based on current knowledge (March 2019) and according to the “Standards and Guidelines for the Interpretation of Sequence Variants” by the ACMG 2015. Results About 84 distinct (likely) pathogenic variants identified in 127 patients were reinterpreted. In 12 variants (12/84, 14.3%), classification changed from (likely) pathogenic to variant of unknown significance (VUS). One of these variants was a hypomorphic allele escaping the standard variant classification. Individuals with variants that downgraded to VUS after reevaluation showed significantly lower Schwartz scores and QTc intervals compared to individuals with unchanged variant characterization. Conclusion This finding confirms genetic variant interpretation as a dynamic process and underlines the importance of ongoing genetic counseling, especially in LQTS patients with minor clinical criteria.

The Efficacy of Beta-Blockers in Patients With Long QT Syndrome 1–3 According to Individuals’ Gender, Age, and QTc Intervals: A Network Meta-analysis

“…The rate of CEs among LQT1 and LQT2 patients in post-adolescence was not presented due to a lack of sufficient evidence ( Figure 2C). Thus, appropriate stratification in terms of the above factors should be performed, in order to guide clinical decision-making for BBs therapy and improve the prognosis of LQTS with the minimum adverse-events (Migdalovich et al, 2011;Westphal et al, 2020).…”

“…We furthermore systematically evaluated the efficacy of BBs therapy in LQTS with different ages, genders, and QTc intervals, as well as genetic subtypes ( Bohnen et al, 2017 ). It is well-established that the rate of CEs in LQTS patients is closely correlated with age and sex ( Wang and Wu, 2004 ). Previous reports have indicated that the risk of fatal events in LQTS is higher in boys than girls during childhood ( Goldenberg et al, 2008 ).…”

“…3) Studies that did not involve a comparison of efficacy among the four BBs. 4) Studies that provided insufficient and unqualified data ( Figure 1A ) ( Moss et al, 2000 ; Conrath et al, 2002 ; Chatrath et al, 2004 ; Priori et al, 2004 ; Wang and Wu, 2004 ; Goldenberg et al, 2008 ; Shimizu et al, 2009 ; Vincent et al, 2009 ; Goldenberg et al, 2010 ; Chockalingam et al, 2012 ; Goldenberg et al, 2012 ; Abu-Zeitone et al, 2014 ; Koponen et al, 2015 ; Steinberg et al, 2016 ; Wilde et al, 2016 ; Mazzanti et al, 2018 ).…”

Clinical impact of rare variants associated with inherited channelopathies: a 5-year update

“…In a study focused on a cohort of children diagnosed with LQTS, 66.66% of VUS were reclassified as LP/P (Bennett et al 2019). In contrast, another study reported 14.3% of variants previously classified as LP/P were downgraded to VUS (Westphal et al 2020). This ambiguity reinforces the need for additional studies focused on a proper reinterpretation, especially if variants were not originally classified following ACMG recommendations (Campuzano et al 2020a, b;VanDyke et al 2020).…”

Clinical Impact of Rare Variants Associated with Inherited Channelopathies: A Five-Year Update

“…In a study focused on a cohort of children diagnosed with LQTS, 66.66% of VUS were reclassi ed as LP/P (Bennett et al, 2019). In contrast, another study reported 14.3% of variants previously classi ed as LP/P were downgraded to VUS (Westphal et al, 2020). This ambiguity reinforces the need for additional studies focused on a proper reinterpretation, especially if variants were not originally classi ed following ACMG recommendations (Campuzano, Sarquella-Brugada, Fernandez-Falgueras, et al, 2020, VanDyke et al, 2020.…”