Abstract 18478: Association of Family History and Cardiomyopathy-Associated Gene Variants of Unknown Significance in Ethnic Minority Patients With Early Onset Atrial Fibrillation
Bibliographic record
Abstract
Introduction: Underrepresentation of ethnic minorities in genetic studies can complicate interpretation of variants of unknown significance (VUS) in these groups. Likely pathogenic or pathogenic (LP/P) cardiomyopathy (CM) gene variants are associated with early onset-atrial fibrillation (EOAF) in a cohort of predominantly European ancestry, but prevalence in minorities, and the role of VUS, is unclear. Three-generation family history (FH) may provide insight into the potential pathogenicity of VUS in ethnic minorities. Hypothesis: In patients with EOAF and low comorbidity burden carrying CM VUS, does positive FH suggest variant pathogenicity? Aims: To determine whether CM gene VUS in ethnic minority probands with EOAF are associated with a FH of arrhythmia, stroke, or heart failure. Methods: Of 301 individuals from the University of Illinois Health Multi-Ethnic AF Registry who underwent whole exome sequencing, we identified 89 with either LP/P variant, positive FH from medical records, or AF diagnosis age ≤55 years and ≤2 comorbidities. We examined 22 genes strongly associated with CM and graded pathogenicity according to American College of Medical Genetics criteria. A three-generation FH was obtained by contacting probands or family members. Results: A FH was obtained in 36 patients (Figure 1a; median age 52 years, 56% female, 83% African-American, 17% Hispanic/Latinx). LP/P variants were present in 3 (8%) probands, VUS in 10 (28%), and likely benign/benign (LB/B) or no variant in 23 (64%). A FH of arrhythmia, heart failure, or stroke was present in 27 subjects (75%) with a FH of heart failure more likely in VUS carriers compared to those with LB/B or no variant (70% vs 26%, p=0.02), with no difference in FH of arrhythmia or stroke. Conclusion: Probands with EOAF who carry CM VUS have greater rates of FH of heart failure than those without disease-associated variants. This suggests pathogenicity of CM VUS in ethnic minorities with EOAF.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".