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. 2020 Feb 11;141(6):418-428.
doi: 10.1161/CIRCULATIONAHA.119.043132. Epub 2020 Jan 27.

An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome

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Free PMC article

An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome

Arnon Adler et al. Circulation. .
Free PMC article

Abstract

Background: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.

Methods: Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.

Results: Of 17 genes reported as being causative for LQTS, 9 (AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes (KCNQ1, KCNH2, SCN5A) were curated as definitive genes for typical LQTS. Another 4 genes (CALM1, CALM2, CALM3, TRDN) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene (CACNA1C) had moderate level evidence for causing LQTS.

Conclusions: More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.

Keywords: ClinGen; genetics; long QT syndrome; sudden death.

Figures

Figure 1.
Figure 1.
Disease causality classification and level of evidence scores for genes reported in LQTS. A, Validity scores according to the ClinGen curation framework and final classifications of the Working Group. Genetic and experimental evidence scores of each one of the 3 blinded curating teams are detailed. Complete list of references used for scoring of these genes is available in the supplements. B, Distribution of genes according to classification. *Genes with strong or definitive evidence for causality in LQTS with atypical features. †Genes with definitive evidence for causality in inherited multiorgan syndrome including QT prolongation but only moderate or limited evidence for isolated LQTS. ‡Genes with strong level of evidence for causality in acquired LQTS but only limited or disputed evidence for congenital LQTS.
Figure 2.
Figure 2.
ECGs of typical and atypical LQTS. ECGs of typical broad-based T waves in long QT 1 (A), bifid T waves in long QT 2 (B, enlarged box), and long horizontal ST-segment in long QT 3 (C). D, ECG of a 1-day-old infant found to carry a de novo variant in CALM3 (c.389A>G, p.Asp130Gly). A very prolonged QT interval with 2:1 atrioventricular block (full arrows) and T-wave alternans (hollow arrows) is present. Adapted with permission from Reed et al. E, An ECG demonstrating QT prolongation and negative T waves in precordial leads of a 10-year-old girl homozygous for a loss-of-function variant in TRDN (c.53_56delACAG, p.Asp18Alafs). Adapted with permission from Altmann et al.
Figure 3.
Figure 3.
Composition of LQTS-specific genetic panels. Percentage of genetic panels including genes previously reported as causing LQTS. *Genes with definitive evidence for causality of typical LQTS. †Genes with strong or definitive evidence for causality in LQTS with atypical features. ‡Genes with definitive evidence for causality in multiorgan including QT prolongation but only moderate or limited evidence for isolated LQTS. §Genes with strong level of evidence for causality in acquired LQTS but only limited or disputed evidence for congenital LQTS.

Comment in

  • Reappraisal of LQTS-causing genes.
    Lim GB. Lim GB. Nat Rev Cardiol. 2020 Apr;17(4):200-201. doi: 10.1038/s41569-020-0349-0. Nat Rev Cardiol. 2020. PMID: 32042138 No abstract available.

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