L. Hunt

Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy

Purpose:Genetic testing for hypertrophic cardiomyopathy has been commercially available for almost a decade; however, low mutation detection rate and cost have hindered uptake. This study sought to identify clinical variables that can predict probands with hypertrophic cardiomyopathy in whom a pathogenic mutation will be identified.Methods:Probands attending specialized cardiac genetic clinics across Australia over a 10-year period (2002–2011), who met clinical diagnostic criteria for hypertrophic cardiomyopathy and who underwent genetic testing for hypertrophic cardiomyopathy were included. Clinical, family history, and genotype information were collected.Results:A total of 265 unrelated individuals with hypertrophic cardiomyopathy were included, with 138 (52%) having at least one mutation identified. The mutation detection rate was significantly higher in the probands with hypertrophic cardiomyopathy with an established family history of disease (72 vs. 29%, P < 0.0001), and a positive family history of sudden cardiac death further increased the detection rate (89 vs. 59%, P < 0.0001). Multivariate analysis identified female gender, increased left-ventricular wall thickness, family history of hypertrophic cardiomyopathy, and family history of sudden cardiac death as being associated with greatest chance of identifying a gene mutation. Multiple mutation carriers (n = 16, 6%) were more likely to have suffered an out-of-hospital cardiac arrest or sudden cardiac death (31 vs. 7%, P = 0.012).Conclusion:Family history is a key clinical predictor of a positive genetic diagnosis and has direct clinical relevance, particularly in the pretest genetic counseling setting.Genet Med 15 12, 972–977.Genetics in Medicine (2013); 15 12, 972–977. doi:10.1038/gim.2013.44

Health status of cardiac genetic disease patients and their at-risk relatives

BACKGROUND Health status is an important outcome measure that incorporates multiple dimensions of health, including symptoms, functional status, and psychosocial factors. While health status has been shown to be a predictor for hospital readmission, morbidity and mortality in the heart failure setting, there are limited data in cardiac genetic disease. We examined health status in a number of cardiac genetic disease groups compared to the general Australian population. METHODS A total of 409 individuals were assessed. Individuals with inherited cardiomyopathies [hypertrophic cardiomyopathy (HCM), familial dilated cardiomyopathy (FDC), arrhythmogenic right ventricular cardiomyopathy (ARVC)] and primary arrhythmogenic disorders [long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT)], as well as their first-degree relatives, completed the Medical Outcomes Survey Short Form-36 (SF-36). The physical and mental component scores (PCS and MCS) and SF-6D utility score were assessed. RESULTS Patients with HCM (p<0.001), FDC (p<0.05), and CPVT (p<0.05) were found to have a significantly lower PCS, while patients with LQTS (p<0.01) had a lower MCS. Individuals at risk of HCM (p<0.0001) and genotype positive-phenotype negative HCM patients (p<0.01) both had a higher PCS and utility scores compared to the clinically affected HCM population. Individuals at risk of LQTS had significantly higher PCS than those with a clinical diagnosis of LQTS (p<0.05) and similarly individuals at risk of FDC had significantly higher PCS than FDC patients (p<0.05). In HCM, female gender (p=0.002), presence of co-morbidities (p<0.0001) and higher NYHA functional class (p<0.0001) were predictors of a lower PCS. CONCLUSIONS Patients with a clinical diagnosis of a genetic heart disease have an impaired health status, related to both physical and mental function. Clinical management strategies in such patient groups need to consider health status as an important outcome measure.

Poor psychological wellbeing particularly in mothers following sudden cardiac death in the young.

Aims: Sudden cardiac death (SCD) in the young is a devastating event and often due to an underlying genetic heart disease. Managing these families is complicated by uncertainty regarding clinical management and profound grief. This study sought to evaluate psychological wellbeing and experiences of at-risk relatives following SCD in the young. Methods: Relatives who attended a specialized clinic following the SCD of a relative were invited to complete the Hospital Anxiety and Depression Scale (HADS) and a series of open-ended questions. Primary outcome measures were the HADS anxiety and depression subscales and a thematic qualitative analysis of the open-ended responses was performed. Clinical and genetic data were collected from the medical record. Results: Fifty relatives from 29 families returned surveys. The mean time since death was 4±2 years (mean age at death 23±10 years, 79% males). There was significant impairment in mean anxiety (8.7±4.3, p<0.0001) and depression (5.8±3.6, p<0.0001) scores compared to the general population. Mothers showed significantly impaired anxiety (10.9±4.0, p=0.001) and depression (7.3±3.3, p=0.001) scores, with 53% having an anxiety score above 11 suggesting probable anxiety disorder. Participants revealed a number of factors that have helped and hindered their ability to cope with the death, and their decisions relating to clinical screening. Conclusion: The SCD of a young relative has significant and long-term emotional implications for the family, particularly for the mother.

Delay to diagnosis amongst patients with catecholaminergic polymorphic ventricular tachycardia.

a Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia b Sydney Medical School, University of Sydney, Sydney, Australia c Royal Childrens Hospital, Melbourne, Victoria, Australia d Genetic Health Queensland, Royal Brisbane & Womens Hospital, Brisbane, Queensland, Australia e The Heart Centre for Children, The Childrens Hospital, Westmead, Sydney, NSW, Australia f Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia

Clinical and genetic features of Australian families with long QT syndrome: A registry-based study

Familial long QT syndrome (LQTS) is a primary arrhythmogenic disorder caused by mutations in ion channel genes. The phenotype ranges from asymptomatic individuals to sudden cardiac arrest and death. LQTS is a rare but significant health problem for which global data should exist. This study sought to provide the first clinical and genetic description of Australian families with LQTS.