Elsevier

Heart Rhythm

Volume 12, Issue 11, November 2015, Pages 2325-2331
Heart Rhythm

Contemporary Review
Genetic purgatory and the cardiac channelopathies: Exposing the variants of uncertain/unknown significance issue

https://doi.org/10.1016/j.hrthm.2015.07.002Get rights and content

Abstract

Merriam-Webster’s online dictionary defines purgatory as “an intermediate state after death for expiatory purification” or more specifically as “a place or state of punishment wherein according to Roman Catholic doctrine the souls of those who die in God׳s grace may make satisfaction for past sins and so become fit for heaven.” Alternatively, it is defined as “a place or state of temporary suffering or misery.” Either way, purgatory is a place where you are stuck, and you don’t want to be stuck there. It is in this context that the term genetic purgatory is introduced. Genetic purgatory is a place where the genetic test–ordering physician and patients and their families are stuck when a variant of uncertain/unknown significance (VUS) has been elucidated. It is in this dark place where suffering and misery are occurring because of unenlightened handling of a VUS, which includes using the VUS for predictive genetic testing and making radical treatment recommendations based on the presence or absence of a so-called maybe mutation. Before one can escape from this miserable place, one must first recognize that one is stuck there. Hence, the purpose of this review article is to fully expose the VUS issue as it relates to the cardiac channelopathies and make the cardiologists/geneticists/genetic counselors who order such genetic tests believers in genetic purgatory. Only then can one meaningfully attempt to get out of that place and seek to promote a VUS to disease-causative mutation status or demote it to an utterly innocuous and irrelevant variant.

Section snippets

Discovery of background genetic noise

How have we descended from the promised land of genomic medicine into this place called genetic purgatory? Recall that the original LQTS-causative genes were exposed by genomic linkage studies involving many affected relatives spanning many generations of families afflicted with highly penetrant disease. These linkage studies revealed the chromosome 11p15.5 (KCNQ1), the chromosome 7q35-36 (KCNH2), and the chromosome 3p21-24 (SCN5A) loci as disease loci for LQTS with incredibly high statistical

Background genetic noise on steroids

Subsequent to these initial reverse experiments that subjected more healthy blood donors than robust LQTS cases to DNA Sanger sequencing through the primary LQTS-susceptibility genes, the various exome-sequencing projects (1000 Genomes; the National Heart, Lung, and Blood Institute’s Exome Sequencing Project [ESP]; and the Exome Aggregation Consortium [ExAC]) now have exposed fully the extent of background genetic noise not just in KCNQ1, KCNH2, SCN5A, and RYR2 but in all genes. Table 1 shows

Deep genetic purgatory for variants within minor disease-susceptibility genes

Table 1 summarizes the signal-to-noise ratio for the 4 canonical channelopathy genes: KCNQ1, KCNH2, SCN5A, and RYR2. It is critical to remember that these impressive ratios are realized only when testing a patient in whom there is a high index of suspicion for the disease being tested. Although genetic purgatory is a possible destination for rare variants localizing to even these major disease genes, as illustrated previously, rare variants that localize to the minor genes place us deeper into

The danger of a “my genetic test panel is bigger than yours” kind of mentality

This brings us to an interesting paradox with respect to technological advances. Fifteen years ago, research-based genetic testing was coupled strongly to the phenotype where genotype-anticipated genetic testing was performed. For example, a patient with QT prolongation, swimming-triggered faints, broad-based T waves, and an abnormal QT response to epinephrine (ie, a strong index of suspicion for LQT1) was subjected to KCNQ1 single-gene testing. In this context, identification of a novel, rare

Phenotype is king, genotype is queen

Until such maturation in knowledge occurs with respect to our ability to intelligently decode our genome, there is an immediate and urgent need to return to foundational principles that the phenotype is king, the genotype is queen, and if you are not sure of the phenotype, don’t go fishing for a genotype. Let’s consider the vital importance of phenotype-guided genetic testing and the consequences that ensue when the genetic test is pursued for weak cases. Rather than having a realized 80% yield

A real-world example of what can happen to patients/families cared for by genetic purgatory atheists/agnostics

Perhaps a real-world case will help drive these critical issues home. The names, ages, and sexes have been altered in the pedigree to protect the innocent and the well-intentioned cardiologist. The index case is Jane Doe, a previously healthy woman without children. Jane Doe died suddenly and unexpectedly as her sentinel event. As is typical in such cases, there was no premortem cardiac evaluation, no ECG. An autopsy was performed and was entirely negative. The medical examiner classified her

References (40)

  • J. Kapplinger et al.

    An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing

    Heart Rhythm

    (2010)
  • G.J. Reed et al.

    CALM3 mutation associated with long QT syndrome

    Heart Rhythm

    (2015)
  • J.D. Kapplinger et al.

    Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test

    Heart Rhythm

    (2009)
  • J.P. Saul et al.

    Rationale and objectives for ECG screening in infancy

    Heart Rhythm

    (2014)
  • J.R. Skinner et al.

    Routine ECG screening in infancy and early childhood should not be performed

    Heart Rhythm

    (2014)
  • R.C. Green et al.

    ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing

    Genet Med

    (2013)
  • M.J. Ackerman

    Cardiac channelopathies: it’s in the genes

    Nat Med

    (2004)
  • D.J. Tester et al.

    Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice

    Circulation

    (2011)
  • N. Hofman et al.

    de Haij S, Mannens MMAM, Lombardi MP, Dit Deprez RHL, van Langen I, Wilde AAM. Yield of molecular and clinical testing for arrhythmia syndromes: report of 15 years’ experience

    Circulation

    (2013)
  • Kapplinger JD, Giudicessi JR, Ye D, Tester DJ, Callis TE, Valdivia CR, Makielski JC, Wilde AA, Ackerman MJ. Enhanced...
  • Cited by (137)

    View all citing articles on Scopus

    Dr. Ackerman reports serving as a consultant for Boston Scientific, Gilead Sciences, Medtronic, and St. Jude Medical and receiving royalties/intellectual property fees from Transgenomic for their FAMILION-LQTS and FAMILION-CPVT genetic tests.

    View full text