James S. Ware

The paper develops an expression-based annotation metric to improve rare variant interpretation by filtering false-positive loss-of-function variants and identifying pathogenic variants in highly expressed exons.

Short-read genome sequencing of 14,891 diverse genomes yields 433,371 structural variants (SVs) for gnomAD; loss-constrained genes also resist duplication, and clinical SV carrier rates are benchmarked.

The paper systematically studies uORF variants in 15,708 genomes, showing they are under strong negative selection and contribute to disease.

The paper analyzes multi-nucleotide variants (MNVs) in 125,748 exomes and 15,708 genomes, identifying their distribution, mutational origins, and functional implications.

The paper quantifies variant pathogenicity in hypertrophic cardiomyopathy using etiological fraction, increasing actionable variant detection by 14-20%.

The paper responds to a critique of their variant filtering method, demonstrating its robustness and highlighting the benefits of using high-resolution variant frequencies for clinical genome interpretation.

CardioClassifier is a decision-support tool for inherited cardiac conditions that improves variant interpretation by integrating disease-specific annotations and case data.

The paper develops a paralog conservation score to identify disease-associated genes and shows that disease variants are enriched at conserved sites across gene families.

The paper presents a statistical framework to filter candidate disease-causing variants using high-resolution variant frequencies, reducing the number of variants under consideration and reclassifying some as pathogenic.