Contemporary ReviewGenetic purgatory and the cardiac channelopathies: Exposing the variants of uncertain/unknown significance issue☆
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
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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.