Abstract 16661: Mutation Type and Number Influence Severity of Pediatric Hypertrophic Cardiomyopathy Phenotype
Bibliographic record
Abstract
Introduction: Improved clinical genetic testing platforms for hypertrophic cardiomyopathy (HCM) have increased detection of pathogenic lesions and of variants of unknown significance (VUS). We assessed the association of mutation type and number with severity and outcomes in pediatric HCM. Methods: All pediatric patients at our institution who were mutation-positive for HCM genes on clinical panel or mutation-specific testing between 2000-14 were included. Patients with pathogenic variants or VUS were further analyzed. Primary outcomes included freedom from major adverse cardiac events (MACE), and severity of LV hypertrophy (LVH) during follow-up. Severe LVH was defined as a septal thickness z-score > +5. Freedom from events between different genotype groups was analyzed by the Kaplan-Meier method and Log-Rank test using STATA v12 (STATACorp, TX). Results: Pathogenic variants or VUS were identified in 79 patients; 50 were male, 62 were familial and 41 were phenotype-negative at presentation. Mutation frequency was highest in MYBPC3 (n=42), and MYH7 (n=30), with 7 patients harboring mutations in other known HCM genes. Thirty four MACE occurred in 27 patients (9 myectomies, 20 ICDs, 3 cardiac arrests, 1 transplant, 1 death). Patients carrying mutations in MYH7 had lower freedom from MACE (HR = 2.42, p= 0.028, fig. 1) and earlier onset of severe LV hypertrophy (HR = 2.11, p=0.025). Ten patients harbored >1 lesion in one or more HCM genes (3 Pathogenic, 7 VUS). Patients with compound mutations had lower freedom from MACE compared to those with a single mutation (HR 2.54, p=0.034), which was due to lower freedom from ICD insertion (HR 4.34, p=0.001). Conclusions: Mutations in MYH7 and occurrence of multiple mutations in one/more HCM genes was associated with higher risk of severe septal hypertrophy and MACE during follow-up in pediatric HCM patients. This suggests that secondary mutations or VUS in HCM genes may inform prognosis even in those with a known pathogenic mutation.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 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) | 0.005 | 0.001 |
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".