Long QT Panel, Sequencing and Deletion/Duplication

Long QT syndrome (LQTS) is characterized by prolongation of the QTc interval and T-wave abnormalities on an electrocardiogram (ECG) in the absence of specific conditions known to lengthen it, such as QT-prolonging drugs. LQTS is associated with tachyarrhythmias, often torsade de pointes (TdP), which may result in syncope, ventricular fibrillation, or sudden cardiac death. Cardiac events may occur from infancy to middle age but are most common in preteens and young adults. Common triggers for cardiac events include exercise, loud noises, emotional stress, or sleep. Not all individuals with a pathogenic variant in an LQTS-associated gene have ECG abnormalities or cardiac symptoms. Syndromic forms of LQTS associated with additional noncardiac features include Andersen-Tawil syndrome, Timothy syndrome, and Jervell and Lange-Nielsen syndrome (JLNS). Molecular confirmation of LQTS in symptomatic individuals or at-risk family members is useful to initiate treatment to prevent syncope or sudden death.

Disease Overview

Clinical Findings

• Syncope
• Cardiac arrest/sudden cardiac death
• ECG abnormalities
  • Prolonged QTc interval on ECG
  • Torsade de pointes
  • T wave alternans
  • Notched T wave
  • Low heart rate for age
• Syndromic forms of LQTS:
  • Andersen-Tawil syndrome
    • Characteristic facial features
    • Periodic paralysis/muscle weakness
  • Timothy syndrome
    • Characteristic facial features
    • Cutaneous syndactyly of hands/feet
    • Neurodevelopmental disorder
  • JLNS
    • Congenital sensorineural hearing loss

Genetics

Genes

Sequencing and deletion/duplication: CACNA1C, CALM1, CALM2, CALM3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, SCN5A, TRDN

Etiology

Pathogenic germline variants in genes associated with LQTS 

Commonly implicated genes with estimated contribution to congenital LQTS:

• KCNQ1 (30-35%)
• KCNH2 (25-30%)
• SCN5A (5-10%)

Penetrance

Variable, influenced by gene involved

Of individuals with a pathogenic variant in an LQTS-associated gene:

• An estimated 25% do not show QTc prolongation on ECG
• Approximately 50% or less have clinical symptoms

Prevalence

1/2,500 for congenital LQTS

Inheritance

Typically, autosomal dominant with incomplete penetrance

Autosomal recessive inheritance for JLNS

Test Interpretation

Methodology

This test is performed using the following sequence of steps:

• Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
• Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline.
• Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
• The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
• Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Clinical Sensitivity

60-75% 

Analytic Sensitivity

For massively parallel sequencing:

Limitations

• A negative result does not exclude a heritable form of LQTS.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of targeted genes
  • Regulatory region and deep intronic variants
  • Breakpoints of large deletions/duplications
• The following may not be detected:
  • Deletions/duplications/insertions of any size by MPS
  • Large duplications less than 3 exons in size
  • Noncoding transcripts
  • Deletions/duplications less than 1kb in the targeted genes
  • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
  • Low-level somatic variants
  • Single exon deletions/duplications in the following exons:
    • •  
    • KCNH2 (NM_000238, NM_172056) 6
    • KCNH2 (NM_001204798, NM_172057) 2
    • TRDN (NM_006073, NM_001251987, NM_001256020, NM_001256021, NM_001256022) 5
    • CALM1 (NM_001363670) 1
  • Duplications in the following genes: CAV3, KCNE1, KCNE2

Genes Tested