Family screening in inherited cardiac conditions: predicting likelihood of a diagnosis

Abstract

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Cardiovascular Research Scholarship awarded by 'Research, Innovation and Development Trust (University of Malta)', kindly donated by Beating Hearts Malta. Scholarship awarded by Tertiary Education Scholarship Scheme. Introduction Family screening is an important pillar in inherited cardiac conditions (ICC), yet the likelihood of disease in screened relatives is difficult to predict. The objective of this study was to create a clinical score to help predict the likelihood of a diagnosis in relatives undergoing screening. Methodology The BEAT-IT national cardiac screening program enrolled 2708 adolescents (14-16 years). Families of probands with a preclinical or clinical diagnosis were offered cardiac screening. Those with an abnormal preliminary screen were further evaluated. Data was analyzed with SPSS v23 using chi squared. P<0.05 was considered statistically significant. Results A total of 19 families were evaluated, 81 family members (60.5% female, mean age 41.1±16.7 at evaluation) underwent cardiac screening because of a preclinical (n=17, 89.4%) or clinical (n=1 HCM, n=1 LQTS) phenotype in the index case. Some (n=8, 9.9%) were labelled with a clinical phenotype (n=5 LQTS, n=2 HCM, n=1 DCM). The highest diagnostic yield was in long QT (55.6%) and HCM (50.0%) probands. All relatives were asymptomatic. Several factors increased the likelihood of a relative being given a diagnosis at screening. The i) presence of a proband phenotype (p<0.001), ii) abnormal screening ECG (p<0.001), iii) abnormal echocardiography suggestive of an ICC (p<0.001), iv) low ejection fraction (p=0.043), v) fibrosis on MRI (p=0.035), vi) likely or definite pathogenic mutation in the proband (p<0.001) and vii) a gene positive relative (p<0.001) were all significantly predictive. Age at evaluation, gender, family history of sudden cardiac death and arrhythmias at screening were not predictive. A relative with ≥3 variables had a higher probability of a clinical diagnosis (72.7% vs 0%, p<0.001). Conclusion A combined clinical and genetic evaluation was able to identify an ICC in 9.9% of screened family members. The presence of ≥3 clinical variables at screening was linked to a higher probability of a diagnosis in relatives. A comprehensive evaluation in relatives with a suspicion of an ICC is necessary useful for diagnostic purposes.