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In recent years the molecular genetics and pathophysiology of long QT syndrome (LQTS), hypertrophic cardiomyopathy (HCM), and Marfan syndrome have been extensively studied. Each disease shows highly variable expression and reduced penetrance of all known phenotypic manifestations1-3 and the diagnosis is often difficult. In addition, the possibility of genotype specific treatment has been raised for LQTS. As a consequence of these diagnostic and therapeutic issues, the role of DNA analysis (genotyping) has become a topic of substantial interest.4-6 Further, as each of these diseases causes unexpected sudden death in children and young adults, often during physical activity, the role of athletic preparticipation screening,7 including DNA testing, is now a widely discussed topic. This editorial will, therefore, examine the role of genotyping for: (1) diagnosis and management of individual patients; and (2) for “genetic screening”, the identification of these diseases in populations such as young athletes.
When is DNA analysis likely to be helpful for the diagnosis and management of patients?
- When the diagnosis is difficult, often because of “reduced penetrance” and “variable expressivity”. Reduced penetrance refers to the absence in some patients of the phenotypic features of the disease. Variable expressivity refers to a high degree of variability of the phenotype.
- When the clinical course varies importantly by genotype or mutation type, and the genetic information will alter treatment strategies. For example, the identification of genotypes predisposing to breast cancer has encouraged some genetically predisposed patients to have prophylactic mastectomy. Or, if one particular genotype in LQTS or HCM was found to be associated with a particularly high rate of ventricular fibrillation and sudden death, prophylactic insertion of an automatic implantable cardioverter-defibrillator (ICD) might be considered. However, if there is no compelling “need to know”, current economic constraints and ethical/privacy issues may limit the interest of governments or insurance companies to pay for DNA testing.
When is genetic screening feasible?
- When the disease causing gene(s) and all mutations are known. Otherwise, patients with the disease, but with mutations of undiscovered genes, will be “false negatives”. This would complicate, rather than clarify, the diagnosis and treatment.
- When the disease is caused by a mutation(s) of a single gene. When mutations of multiple genes are required, called “polygenic disorders”, or when both genetic abnormalities and environmental factors are required in order for the disease to develop, molecular genetic studies may not be fully informative or as useful.
So how can these concepts can be applied to LQTS, HCM, and Marfan syndrome?
Long QT syndrome
Inherited LQTS1 is an autosomal dominant disorder (in Jervell, Lange-Nielsen syndrome the deafness is recessive, but the LQTS is dominant) with an estimated prevalence of 1:5000 persons. It is effectively treated with β blockers, implantable defibrillators, and pacemakers. Five genes which encode cardiac ion channels and about 180 mutations have been reported.4Sporadic cases occur but are uncommon. No mutation is found on genotyping in about 30% of clinically affected patients. Some of these patients may have mutations of undiscovered genes, and some cases may be due to limitations of the analysis techniques. There is tremendous variability of expression and reduced penetrance of the QTc and the symptom phenotypes. For example, fig 1 shows the QTc distribution on baseline ECG of a large number of LQTS gene carriers. Graphs of the characteristic phenotype of HCM and …