Managing uncertainty in inherited cardiac pathologies-an international multidisciplinary survey

Abstract

Multi-gene testing is useful in genetically heterogeneous conditions, including inherited cardiac pathologies. Increasing the number of genes analysed increases diagnostic yield of variants of certain, likely, or uncertain pathogenicity. Concerns exist regarding management of variants of uncertain/likely pathogenicity in conditions of oligogenic inheritance or variable expressivity. We surveyed a sample of colleagues across different specialties and departments internationally to compare management of patients with class 3 or class 4 variants in genes associated with non-syndromic cardiomyopathy or arrhythmia. An electronic survey regarding clinical management of variants ( www.surveymonkey.com/r/cardiacvariants ) was designed and distributed to colleagues internationally via professional bodies and direct email. 150 respondents (88 centres, 27 countries) completed the survey, most of whom were Clinical Geneticists or Genetic Counsellors. Most respondents offer pre-symptomatic testing to asymptomatic relatives of an individual with class 4 or class 5 variants. A minority of respondents offer pre-symptomatic testing for class 3 variants. Considering class 4 variants, 22 (15%) are fully reassuring that the patient with a negative predictive test would not develop the familial phenotype, while 123 (82%) counselled patients about the possibility of variant reclassification. Variability existed between and within centres and specialties. Multiple "free text" comments were provided. Recurring themes including need for multidisciplinary input, technical concerns, and concern regarding duty to review variants of uncertain significance. This study demonstrates that variability in management of likely pathogenic/uncertain variants exists. Close multi-disciplinary input is essential. The development of disorder or gene-specific evidence-based guidelines might ameliorate uncertainty in management.

Fig. 1

Country of practice of respondents

Fig. 2

Proportion of respondents who would offer pre-symptomatic testing of familial variants of different classes to unaffected relatives

Fig. 3

Respondent answers by specialty. a Participant response regarding whether they would be fully reassuring that the asymptomatic individuals having a negative predictive test for familial class 4 variant would not develop the familial phenotype. b Participant response regarding discussing uncertainty about pathogenicity of a class 4 variant with asymptomatic individual having negative predictive test. c Participant response regarding whether they mention potential reclassification of class 4 variant to asymptomatic individuals having negative predictive test. d Participant response regarding referral of asymptomatic individuals having negative predictive test for familial class 4 variant for cardiac assessment. e Participant response regarding whether they recommend discharge of asymptomatic individuals having negative predictive tests for familial class 4 variant to asymptomatic individuals having negative predictive test