HRS Board Review 2025 New Courses (Reviewers Copy)-Workshop 1_Electrocardio_London_2025

Video Transcription

And the correct answer is B. He has no evidence of Long QT syndrome, but further cardiac testing is required.  So there are 73 genes for which reporting of mutations is mandatory when performing whole exome or whole genome sequencing for clinical diagnosis.  And I've listed the reference to the more recent paper. The number of genes has recently been upgraded to 73 from the prior number of 58.  For most inherited diseases, some individuals carry a pathogenic mutation, in other words, they have the affected genotype, without any phenotype.  Frank carries the SCN5A mutation that can cause Long QT syndrome, but he has a normal QTC interval, most likely due to other compensatory genetic or environmental factors.  That's what we call incomplete penetrance, and the formula for incomplete penetrance is the number of people who actually have the phenotype divided by the number of people  who have the genotype being less than one. Frank is at risk for clinical Long QT syndrome, but he doesn't have it.  His EKG does, however, have an old inferior wall myocardial infarction as an incidental finding.  Now, for Frank, coronary disease is likely much more dangerous to him than the risk that he might develop his Long QT syndrome at some point in the future.  So he needs additional testing based on his potential coronary disease. He needs to be risk stratified and treated appropriately.  For the Long QT syndrome risk, he should be told to avoid QT-prolonging drugs. Frank's two other children each have a 50-50 chance of inheriting the mutation.  They should be screened genetically and then clinically if proven to be carriers. While it's possible that the mutation was misclassified and it's actually a benign polymorphism,  it's more likely for the genes and mutations that are reported as pathogenic that it actually  is pathogenic with incomplete penetrance, and that should be the assumption moving forward. On this slide, I've provided a list of the genes that are mandatory reporting genes when  a pathogenic mutation is identified. It includes many of the inherited arrhythmia genes, and it includes many of the cardiomyopathy genes.

Video Summary

Frank carries an SCN5A mutation linked to Long QT syndrome, but currently shows no symptoms, illustrating incomplete penetrance. He has a normal QTC interval, likely due to compensatory factors. His EKG revealed an incidental old myocardial infarction, indicating coronary disease, which poses a higher risk than potential Long QT syndrome. Further cardiac assessment and risk stratification are advised for Frank, with precautions against QT-prolonging drugs. His children have a 50% chance of inheriting the mutation and should be screened. Reporting mutations in 73 mandatory genes is crucial for diagnosing inherited conditions, even with variable phenotypic expression.

Keywords

SCN5A mutation

Long QT syndrome

incomplete penetrance

coronary disease

genetic screening