Family Screening in Dilated Cardiomyopathy
- In this cohort study, family screening (clinical and genetic testing) for relatives of patients with familial dilated cardiomyopathy identified a genetic predisposition or overt disease in one-third of relatives.
- Relatives without likely pathogenic/pathogenic variants and normal baseline ECG/TTE testing were at low risk for development of clinical disease in follow-up. Over one-half of relatives screened were low risk based on this testing, which may have implications for future follow-up.
For relatives of patients with familial dilated cardiomyopathy (FDC) participating in family screening, what are the predictors, prevalence, and incidence of disease?
This was a retrospective, cohort study of families screened for FDC through a regional network of inherited cardiomyopathy clinics in Copenhagen, Denmark, from 2006 to 2020. Families were included if at least one first-degree relative of a proband underwent screening. Clinical data from probands and relatives were collected, which included demographics, history and physical exam, electrocardiogram (ECG) findings, transthoracic echocardiogram (TTE) findings, other imaging findings, arrhythmia monitoring, hospitalizations, and genetic testing results.
Affected relatives at screening were initiated on heart failure treatments. Relatives with borderline symptoms or objective findings were followed up at short intervals. No clinical follow-up testing was required for healthy genotype-negative relatives from likely pathogenic/pathogenic (LP/P) variant families. The remaining relatives were offered follow-up testing in 3-5 years, or sooner if new symptoms developed.
A total of 211 families with FDC were included in the study. The participants included 211 probands and 563 relatives (65% of 870 relatives eligible participated). Relatives were a mean age of 38 years (standard deviation ± 17 years) at first visit, 50% female sex, and followed for a median of 5.3 years (interquartile range 2.7-8.8 years).
At baseline clinical screening, 124 of 563 relatives (22%) from 90 of 211 families (43%) met clinical diagnostic criteria for FDC. The prevalence of FDC in affected relatives increased with age. Genetic screening was completed for 186 of 211 (88%) families. LP/P variants were discovered in 69 families (genetic yield 37%). Cascade genetic testing identified 43 relatives with LP/P variants but did not meet FDC criteria at baseline screening. Testing also revealed 58 relatives that were genotype-negative (12% of 439 relatives without FDC at baseline). The combined clinical and genetic testing yield for FDC or a genetic predisposition was 167 of 563 (30%).
During follow-up, 45 of 439 (10%) relatives without FDC at baseline eventually met clinical diagnostic criteria for FDC (incidence rate 2.0% per person-year). The strongest predictor of developing clinical FDC during this follow-up period was carrying a LP/P variant (incidence 10% per person-year). None of the genotype-negative patients developed disease. Relatives with abnormal baseline ECG or TTE findings (incidence 4.7% per person-year) and participants of male sex (incidence 3.1% per person-year) were also at higher risk. Based on these predictors, 326 of 563 (58%) relatives could have been identified as low risk for FDC (no LP/P variants and no abnormal ECG/TTE findings) with baseline screening.
Clinical and genetic screening for relatives of patients with FDC identified a genetic predisposition or clinical FDC in approximately one-third of participants. Over one-half of the screened relatives had no LP/P variants and normal baseline ECG/TTE, which was associated with a low risk for development of FDC in follow-up.
For patients with cardiomyopathy and a suspected genetic etiology, family screening with clinical and genetic testing is important in identifying relatives at risk for or with subclinical disease. This cohort study demonstrated that there is great value in clinical testing alone, which identified 22% of relatives as having diagnostic criteria for FDC. Additionally, abnormal baseline ECG and TTE findings were predictors of future development of FDC. Genetic testing was useful in this study as well, helping to identify additional relatives at risk as carriers of LP/P variants and importantly identifying genotype-negative relatives at low-risk for developing disease (none during the follow-up period). These findings are important, as they highlight the value of family screening and suggest a role for reducing the frequency of follow-up or screening for low-risk relatives.
Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Valvular Heart Disease, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Echocardiography/Ultrasound
Keywords: Arrhythmias, Cardiac, Cardiomyopathy, Dilated, Cardiomyopathy, Hypertrophic, Familial, Diagnostic Imaging, Echocardiography, Electrocardiography, Family, Genetic Predisposition to Disease, Genetic Testing, Heart Failure, Physical Examination, Risk, Secondary Prevention
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