Identification of Cadherin 2 ( <i>CDH2</i> ) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy
Bibliographic record
Abstract
Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous condition caused by mutations in genes encoding desmosomal proteins in up to 60% of cases. The 40% of genotype-negative cases point to the need of identifying novel genetic substrates by studying genotype-negative ARVC families. Methods and Results— Whole exome sequencing was performed on 2 cousins with ARVC. Validation of 13 heterozygous variants that survived internal quality and frequency filters was performed by Sanger sequencing. These variants were also genotyped in all family members to establish genotype–phenotype cosegregation. High-resolution melting analysis followed by Sanger sequencing was used to screen for mutations in cadherin 2 ( CDH2 ) gene in unrelated genotype-negative patients with ARVC. In a 3-generation family, we identified by whole exome sequencing a novel mutation in CDH2 (c.686A>C, p.Gln229Pro) that cosegregated with ARVC in affected family members. The CDH2 c.686A>C variant was not present in >200 000 chromosomes available through public databases, which changes a conserved amino acid of cadherin 2 protein and is supported as the causal mutation by parametric linkage analysis. We subsequently screened 73 genotype-negative ARVC probands tested previously for mutations in known ARVC genes and found an additional likely pathogenic variant in CDH2 (c.1219G>A, p.Asp407Asn). CDH2 encodes cadherin 2 (also known as N-cadherin), a protein that plays a vital role in cell adhesion, making it a biologically plausible candidate gene in ARVC pathogenesis. Conclusions— These data implicate CDH2 mutations as novel genetic causes of ARVC and contribute to a more complete identification of disease genes involved in cardiomyopathy.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".