Patients With Hypertrophic Cardiomyopathy and Normal Genetic Investigations Have Few Affected Relatives
Key result
Genotype-positive HCM is linked to a ~16-fold higher yield of affected relatives at screening.
- P<0.001
- n=225
Journal of the American College of Cardiology published a graphical abstract
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Why the study?
The value of family screening in relatives of HCM index patients with normal genetic investigations of recognized HCM genes is largely unknown.
Does genotype-positive status predict familial disease expression and adverse clinical outcomes in patients with hypertrophic cardiomyopathy?
Key Points
- To evaluate the yield of clinical family screening and describe clinical characteristics of affected relatives of hypertrophic cardiomyopathy index patients who have normal genetic testing.
- Consecutive and unrelated hypertrophic cardiomyopathy index patients underwent clinical and genetic investigations.
- Relatives of index patients lacking pathogenic or likely pathogenic variants in recognized genes were invited for clinical evaluation (N=751 evaluated of 938 invited; median age 44 years; 5 years of follow-up).
- A normal genetic investigation was observed in 60% (270 of 453) of hypertrophic cardiomyopathy index patients.
- Among evaluated relatives, 5% (34 of 751) were diagnosed with hypertrophic cardiomyopathy at baseline and 0.3% (2 of 717) developed the disease during 5 years of follow-up, with a median age at diagnosis of 57 years (IQR: 51-70 years).
- Two-thirds (22 of 36) of affected relatives were identified through family screening and 14 of 36 had prior diagnoses; none experienced adverse disease complications and the risk of sudden cardiac death was low.
Study Design
Type
Cohort (n=225)
Multicenter
Yes
Structured PICO
Does genotype-positive status predict familial disease expression and adverse clinical outcomes in patients with hypertrophic cardiomyopathy?
P
Population
225 unrelated index patients (mean age 46, 32.4% female) with primary hypertrophic cardiomyopathy evaluated in Sweden and followed for a mean of 16.4 years.
E
Exposure
Genotype-positive status (carriers of pathogenic or likely pathogenic variants in cardiomyopathy-associated genes, primarily MYBPC3 and MYH7)
C
Comparator
Genotype-negative status (no reportable genetic variants)
O
Outcome
HCM phenotype in family members at initial clinical screeninghard clinical
Main Result
Absolute Event Rate: 43% vs 2.7%
p-value: p=<0.001
Limitations
- Retrospective observational design
- Survivor bias due to inclusion of patients diagnosed many years prior to the study period
- Low number of events limiting multivariable analysis
- Potential selection or reporting bias regarding family history of sudden cardiac death
- Survivor bias
- Low number of clinical events
- Selection or reporting bias in eliciting family history
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Importantly, however, although the overall yield of screening at an individual patient level was low, a diagnosis was made as a result of family screening in more than 10% of families, which is not insignificant.”
“The current recommendation of serial clinical screening of first-degree relatives of all HCM patients has recently been challenged.”
Implication
Genotype-negative HCM patients have a substantially lower probability of clinically affected relatives than genotype-positive patients, which can inform cascade family screening strategies.
Abstract
BACKGROUND Current guidelines recommend that relatives of index patients with hypertrophic cardiomyopathy (HCM) are offered clinical investigations to identify individuals at risk of adverse disease complications and sudden cardiac death. However, the value of family screening in relatives of index patients with a normal genetic investigation of recognized HCM genes is largely unknown. OBJECTIVES The purpose of this study was to perform family screening among relatives of HCM index patients with a normal genetic investigation to establish the frequency of familial disease and the clinical characteristics of affected individuals. METHODS Clinical and genetic investigations were performed in consecutive and unrelated HCM index patients. Relatives of index patients who did not carry pathogenic/likely pathogenic variants in recognized HCM genes were invited for clinical investigations. RESULTS In total, 60% (270 of 453) of HCM index patients had a normal genetic investigation. A total of 80% of their relatives (751 of 938, median age 44 years) participated in the study. Of these, 5% (34 of 751) were diagnosed with HCM at baseline, whereas 0.3% (2 of 717 [751-34]) developed the condition during 5 years of follow-up. Their median age at diagnosis was 57 years (IQR: 51-70 years). Two-thirds (22 of 36) were diagnosed following family screening, whereas one-third (14 of 36) had been diagnosed previously because of cardiac symptoms, a murmur, or an abnormal electrocardiogram. None of the affected relatives experienced adverse disease complications. The risk of SCD was low. CONCLUSIONS Systematic family screening of index patients with HCM and normal genetic investigations was associated with a low frequency of affected relatives who appeared to have a favorable prognosis.
Discussion
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Cite This Study
Nielsen et al. (2023) conducted a cohort in Hypertrophic Cardiomyopathy (n=225). Genotype-positive status (pathogenic/likely pathogenic variants) vs. Genotype-negative status (no reportable genetic variants) was evaluated on HCM phenotype in family members at initial clinical screening (p=<0.001). Genotype-positive status in hypertrophic cardiomyopathy index patients was associated with a significantly higher frequency of clinically affected relatives at initial screening compared to genotype-negative status (43% vs 2.7%, p<0.001).