Inherited heart rhythm disorders (IHRD) are uncommon conditions that are often not detected until the tragic sudden unexpected death (SUD) of a seemingly healthy young individual. These conditions include Long QT Syndrome (LQTS), Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), and Brugada Syndrome. Due to their rarity and wide variety of presentations, IHRD are often not suspected and, even when they are considered, can be difficult to diagnose. As a result, many people are left undiagnosed, with a potential “time bomb” ticking with every heartbeat. In early 2013, the British Columbia Inherited Arrhythmia Program (BC IAP) was launched by a team of adult and  paediatric electrophysiologists, medical geneticists, genetic counselors, clinical and research nurses, and other health professionals. Unfortunately, warning signs of IHRD may be subtle, missed or nonexistent, and thus cardiac arrest or SUD is often the reason for referral to the BC IAP. In an effort to increase awareness and prevent SUD, the BC IAP provides clinical consultation and genetic counseling to index cases (probands) and their families. The comprehensive, multidisciplinary program specializes in the diagnosis, management, and innovative research of IHRD. Here, the proband and their family are supported through the process of diagnostic testing that screens each first degree family member and helps find answers, reveals potential inherited arrhythmia conditions, and potentially plays a crucial role in future research of these rare and incompletely defined conditions.

Diagnostic considerations and issues

IHRD are relatively new to the clinical scene; though they have been around for decades, much of what we know has been discovered in the last 30 years. Most physicians are not familiar with the subtle diagnostic signs on the patient’s electrocardiogram (ECG), and often attribute potential warning symptoms (fainting, dizziness) to more common ailments such as vasovagal syncope (the common faint), epilepsy, or puberty. Specifically, most physicians, including many cardiologists, have difficulty accurately assessing the QT interval, hence a sudden collapse caused by Long QT Syndrome (LQTS) may

be misdiagnosed as epilepsy in children [2]. Both conditions can present as episodic loss of consciousness, sometimes triggered by sudden, startling noises; epilepsy is more than ten times as prevalent as LQTS [3, 4]. However, with proper and informed consultation, elements such as a family history of sudden death, bystander history of collapse followed by apparent seizure activity and potentially concerning ECG findings can distinguish LQTS from epilepsy.

Genetic considerations

Most IHRD are inherited in an autosomal manner, caused by mutations, or “typos”, in specific areas of the DNA code (genes). A new mutation can occur in any generation, and can be passed from parent to child. IHRD are typically transmitted in an autosomal dominant fashion, meaning only one copy of an altered or “mutated” gene is required to result in the condition predisposing to cardiac arrest or sudden death. Therefore, an affected individual has a 50% chance of passing on the genetic predisposition to the specific IHRD to each of his or her children. However, of two family members with an identical genetic mutation, one may present a phenotype including symptoms while another may be asymptomatic with much less evidence that they are affected [9, 10]. This is due to phenomena called reduced penetrance and variable expressivity. Reduced penetrance means that not every patient with a known pathogenic mutation shows features of the disease. Variable expressivity refers to the wide range and combinations of sign and symptoms seen in patients with IHRD.

With recent genetic sequencing advances and the familial nature of these conditions, genetic testing commonly plays a large role in the diagnosis of IHRD. As tempting as it can be to genetically test every potential IHRD patient, there are still a number of drawbacks to be considered. Besides the substantial financial limitation (testing costs around $3000 for the proband), there are social, psychological, and scientific considerations. Social concerns stem from insurance and employment discrimination; the tested individual may be unable to obtain life insurance or pursue certain careers. This is also true for clinical cardiac testing, and asymptomatic family members should be aware of this potential before undergoing genetic screening. Compounded with the variable penetrance and expressivity of these conditions, asymptomatic mutation carriers may be unnecessarily discriminated against. The alternative perspective includes confirmation one does not carry the family mutation, which may have a positive effect on insurance eligibility. The psychosocial burden of living with a gene mutation predisposing to sudden death also needs to be considered before genetic testing. Families are commonly referred only after a tragic death, and although there is no control over which copy of a gene is passed on to a child, a parent may feel immense guilt if found to have the mutation identified in the deceased. Finally, there is also a substantial scientific limitation as only a modest proportion of patients will harbor a disease-causing mutation (5-75% based on underlying condition) [11-13]. In addition, a genetic test may reveal a disease-causing mutation, a variant of unknown significance (VUS) (a “maybe” mutation), or no known mutation. These VUS may represent a minor difference in one’s genes leading to individuality; however, they could also be the explanation for an IHRD. Patients, particularly those undergoing predictive or presymptomatic testing, should consider whether they wish to accept awareness of what lies within their genes before delving into genetic testing. However, unlike many other genetic disease models for presymptomatic testing where no treatment is available [14], the recognition of a ‘predisposition to’ an IHRD may allow for preventative treatment, such as avoidance of QT prolonging drugs and the use of beta blockers in LQTS1 [15].

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This article is adapted from Mikyla Janzen, Shubhayan Sanatani, Karen A Gibbs, Saira S Mohammed, Julie Hathaway, Laura Arbour, Andrew D Krahn, Inherited heart rhythm disorders: Diagnostic dilemmas after the sudden death of a young family member. Source article. This work is licensed under a Creative Commons Attribution 3.0 License.