Principles of Genetic Counseling in Inherited Heart Conditions.

Cardiac genetic counseling is the process of helping individuals adapt to a personal diagnosis or family history of an inherited heart condition. The process is shown to benefit patients and includes specialized skills, such as counseling children and interpreting complex genetic results. Emerging areas include: evolving service delivery models for caring for patients and communicating risk to relatives, new areas of need including postmortem molecular autopsy, and new populations of individuals found to carry a likely pathogenic/pathogenic cardiac variant identified through genomic screening. This article provides an overview of the cardiac genetic counseling process and evolving areas in the field.

Cardiomyopathies and Genetic Testing in Heart Failure: Role in Defining Phenotype-Targeted Approaches and Management.

Cardiomyopathies represent an important cause of heart failure, often affecting young individuals, and have important implications for relatives. Genetic testing for cardiomyopathies is an established care pathway in contemporary cardiology practice. The primary cardiomyopathies where genetic testing is indicated are hypertrophic, dilated, arrhythmogenic, and restrictive cardiomyopathies, with left ventricular noncompaction as a variant phenotype. Early identification and initiation of therapies in patients with inherited cardiomyopathies allow for targeting asymptomatic and presymptomatic patients in stages A and B of the American College of Cardiology/American Heart Association classification of heart failure. The current approach for genetic testing uses gene panel-based testing with the ability to extend to whole-exome and whole-genome sequencing in rare instances. The central components of genetic testing include defining the genetic basis of the diagnosis, providing prognostic information, and the ability to screen and risk-stratify relatives. Genetic testing for cardiomyopathies should be coordinated by a multidisciplinary team including adult and pediatric cardiologists, genetic counsellors, and geneticists, with access to expertise in cardiac imaging and electrophysiology. A pragmatic approach for addressing genetic variants of uncertain significance is important. In this review, we highlight the indications for genetic testing in the various cardiomyopathies, the value of early diagnosis and treatment, family screening, and the care process involved in genetic counselling and testing.

Uptake of Predictive Genetic Testing and Cardiac Evaluation for Children at Risk for an Inherited Arrhythmia or Cardiomyopathy.

Predictive genetic testing in minors should be considered when clinical intervention is available. Children who carry a pathogenic variant for an inherited arrhythmia or cardiomyopathy require regular cardiac screening and may be prescribed medication and/or be told to modify their physical activity. Medical genetics and pediatric cardiology charts were reviewed to identify factors associated with uptake of genetic testing and cardiac evaluation for children at risk for long QT syndrome, hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. The data collected included genetic diagnosis, clinical symptoms in the carrier parent, number of children under 18 years of age, age of children, family history of sudden cardiac arrest/death, uptake of cardiac evaluation and if evaluated, phenotype for each child. We identified 97 at risk children from 58 families found to carry a pathogenic variant for one of these conditions. Sixty six percent of the families pursued genetic testing and 73% underwent cardiac screening when it was recommended. Declining predictive genetic testing was significantly associated with genetic specialist recommendation (p < 0.001) and having an asymptomatic carrier father (p = 0.006). Cardiac evaluation was significantly associated with uptake of genetic testing (p = 0.007). This study provides a greater understanding of factors associated with uptake of genetic testing and cardiac evaluation in children at risk of an inherited arrhythmia or cardiomyopathy. It also identifies a need to educate families about the importance of cardiac evaluation even in the absence of genetic testing.

Two mtDNA mutations 14487T>C (M63V, ND6) and 12297T>C (tRNA Leu) in a Leigh syndrome family.

Mitochondrial cytopathies are characterized by a large variability of clinical phenotypes and severity. The 14487T>C mutation in mtDNA has been recently described to be associated with Leigh syndrome. The 12297T>C mutation has been described in isolated dilated cardiomyopathy patients. Here, we report a family with multiple members who harbor both mutations, with only a few individuals who are affected with Leigh syndrome. Mitochondrial whole genome sequencing analysis in the proband's muscle specimen detected two nearly homoplasmic mutations: 14487T>C (M63V in ND6) and 12297T>C in the tRNA (Leu) (CUN) gene. These two mutations were also detected in the blood, urine sediments, hair follicles, and buccal swab samples of all matrilineal relatives tested. All individuals tested were nearly homoplasmic for the 12297T>C mutation, but had variable degrees of heteroplasmy for 14487T>C. We also screened for the frequency of these two mutations. Of 268 patients with Leigh or Leigh-like disease, one case was found to harbor the 14487T>C mutation (0.3%), and one had the 12297T>C mutation (0.3%). Neither mutation was detected in the 88 patients meeting MELAS syndrome criteria nor in the 56 patients with respiratory chain complex I or I+III deficiency. In conclusion, the 14487T>C mutation appears as the primary etiology of Leigh syndrome in this family, demonstrating the high level of heteroplasmy needed for a clinically significant phenotype with this mutation. The 12297T>C mutation was not associated with dilated cardiomyopathy for the family members who were clinically evaluated and who were shown by testing to be nearly homoplasmic for that mutation.