Massively Parallel Sequencing / Exonic Oligonucleotide-based CGH Microarray
- Use to confirm diagnosis of LQTS in symptomatic individuals.
- Use for presymptomatic testing in individuals with family history of LQTS or sudden cardiac death.
Massively Parallel Sequencing
Preferred test to assess for hereditary form of cardiomyopathy or arrhythmia.
Polymerase Chain Reaction/Sequencing
- Assess for a familial sequence variant previously identified in a family member.
- A copy of the relative's genetic laboratory report documenting the familial variant is required.
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
- Andersen-Tawil syndrome
Genetics
Genes
Sequencing and deletion/duplication: CACNA1C, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, SCN5A
Sequencing only: CALM1, CALM2
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 Description
Clinical Sensitivity
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
- Deletions/duplications of CALM1 and CALM2
- Noncoding transcripts
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- 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) 13
- KCNQ1 (NM_000218) 16
- KCNQ1 (NM_181798) 1
Analytical Sensitivity
For massively parallel sequencing:
Variant Class | Analytical Sensitivity (PPA) Estimatea (%) | Analytical Sensitivity (PPA) 95% Credibility Regiona (%) |
---|---|---|
SNVs |
99.2 |
96.9-99.4 |
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
Deletions 11-44 bp |
99.9 |
87.8-100 |
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
Insertions 11-23 bp |
99.9 |
62.1-100 |
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
Gene | MIM # | Associated Disorder(s) | Inheritance |
---|---|---|---|
CACNA1C |
114205 |
LQTS 8 |
AD |
CALM1 |
114180 |
LQTS 14 |
AD |
CALM2 |
114182 |
LQTS 15 |
AD |
CAV3 |
601253 |
LQTS 9 |
AD |
KCNE1 |
176261 |
JLNS2 |
AR |
LQTS 5 |
AD |
||
KCNE2 |
603796 |
Familial atrial fibrillation 4 |
AD |
KCNH2 |
152427 |
LQTS 2 |
AD |
KCNJ2 |
600681 |
Andersen-Tawil syndrome |
AD |
KCNQ1 |
607542 |
Familial atrial fibrillation 3 |
AD |
JLNS 1 |
AR |
||
SCN5A |
600163 |
Progressive/nonprogressive heart block |
AD |
Sick sinus syndrome 1 |
AR |
||
AD, autosomal dominant; AR, autosomal recessive; CPVT, catecholaminergic polymorphic ventricular tachycardia; SQTS, short QT syndrome |
References
-
31983240
Adler A, Novelli V, Amin AS, et al. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation. 2020;141(6):418-428.
PubMed -
GeneReviews - Long QT Syndrome
Alders M, Bikker H, Christiaans I. Long QT syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2021. [Last Update: Feb 2018; Accessed: Feb 2021]
Online