D.N. Cooper

Context-dependent variant interpretation from Mendelian disease to genetic predisposition: a proof-of-concept using LPL

This paper proposes a context-dependent framework for variant interpretation by analyzing LPL loss-of-function variants, showing how residual activity levels influence clinical outcomes.

When splicing is not all or none: GT>GC 5' splice-site variants as a model for intermediate effects and challenges in variant classification

The paper examines GT>GC 5' splice-site variants, showing they can retain wild-type transcript and challenge variant classification.

Ancestry-specific performance of variant effect predictors in clinical variant classification

The paper evaluates how well variant effect predictors perform across different genetic ancestries, finding comparable performance across major groups after accounting for allele frequency.

Predicting interaction-specific protein-protein interaction perturbations by missense variants with MutPred-PPI

MutPred-PPI predicts interaction-specific effects of missense variants using graph attention networks, showing strong performance on both seen and unseen proteins.

Disease-specific variant pathogenicity prediction using multimodal biomedical language models

This paper introduces a deep learning framework for predicting disease-specific variant pathogenicity, showing improved accuracy over existing methods.

Critical assessment of missense variant effect predictors on disease-relevant variant data

The paper evaluates missense variant effect predictors using CAGI6 data, finding strong performance across settings and highlighting biases in some predictors.

Alu insertion-mediated dsRNA structure formation with pre-existing Alu elements as a novel disease-causing mechanism

The paper identifies a novel disease mechanism where an Alu insertion forms dsRNA structures with pre-existing intronic Alu elements, leading to reduced SPINK1 mRNA expression.

Genetic evidence for T-wave area from 12-lead electrocardiograms to monitor cardiovascular diseases in patients taking diabetes medications

The paper identifies genetic associations between diabetes medications and ECG features, finding a causal link between medication use and reduced T-wave area in lead aVR, increasing risk of ischemic heart disease and coronary atherosclerosis.

Genome-wide prediction of pathogenic gain- and loss-of-function variants from ensemble learning of diverse feature set

LoGoFunc predicts pathogenic gain- and loss-of-function variants using ensemble learning with diverse biological features, outperforming existing tools.

Integrating gene mutation spectra from tumors and the general population with gene expression topological networks to identify novel cancer driver genes

DGAT-cancer integrates mutation spectra and gene expression networks to identify 571 novel cancer drivers, with EEF1A1 validated as a glioma driver.

A comprehensive knowledgebase of known and predicted human genetic variants associated with COVID-19 susceptibility and severity

The paper compiles 820 host genetic variants associated with COVID-19 susceptibility, develops a machine learning classifier to predict severity variants, and creates a web-based resource for exploring these variants.

An efficient error correction and accurate assembly tool for noisy long reads

NextDenovo corrects noisy Nanopore reads faster and more accurately than Canu and Necat; its maize and 35 human-genome assemblies are more contiguous, with fewer misassemblies, than Flye's.

Validation of the ACMG/AMP guidelines-based seven-category variant classification system

The paper validates a seven-category variant classification system by testing its applicability across different Mendelian disease contexts and demonstrates its utility for variant interpretation and genetic counseling.

Genome-wide detection of human variants that disrupt intronic branchpoints

The paper introduces BPHunter, a computational tool to detect intronic variants disrupting branchpoints, identifies known and novel mutations, and validates them experimentally.

A proposed general variant classification framework using chronic pancreatitis as a disease model

The paper proposes a new variant classification framework for chronic pancreatitis, introducing new categories to better classify variants in disease-causing and predisposing genes.

The reversion variant (p.Arg90Leu) at the evolutionarily adaptive p.Arg90 site in CELA3B predisposes to chronic pancreatitis

The paper identifies p.Arg90Leu as a variant in CELA3B associated with chronic pancreatitis, reverting to an ancestral allele and confirming CELA3B's role in CP etiology.

Identification of Discriminative Gene-level and Protein-level Features Associated with Gain-of-Function and Loss-of-Function Mutations

The paper identifies gene- and protein-level features distinguishing gain-of-function and loss-of-function mutations using NLP and machine learning on a new database of pathogenic mutations.

AMELIE 3: Fully Automated Mendelian Patient Reanalysis at Under 1 Alert per Patient per Year

AMELIE 3 automatically reanalyzes undiagnosed Mendelian disease patients using new literature, achieving 80% diagnostic yield with 0.5-1 alerts per patient per year.

MutPred2: inferring the molecular and phenotypic impact of amino acid variants

MutPred2 identifies pathogenic amino acid variants, predicts their molecular mechanisms, and validates their functional impact in neurodevelopmental disorders.

Developmental gene expression differences between humans and mammalian models

The paper identifies developmental gene expression differences between humans and mammalian models, finding that half of human genes differ from their mouse orthologs in temporal trajectories, particularly for disease-related genes.

Identifying novel high-impact rare disease-causing mutations, genes and pathways in exomes of Ashkenazi Jewish inflammatory bowel disease patients

The paper identifies 7 novel IBD-causing genes in Ashkenazi Jewish IBD patients using exome sequencing and analyzes their overlap with early-onset IBD and other diseases.

PIVOTAL: Prioritizing variants of uncertain significance with spatial genomic patterns in the 3D proteome

PIVOTAL prioritizes variants of uncertain significance using 3D proteome spatial patterns, predicting pathogenicity for 140,000 VUS and providing a web tool for analysis.

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

The paper identifies 166 dispensable human genes with common loss-of-function variants that show relaxed selective constraints and some evidence of positive selection.

AMELIE 2 speeds up Mendelian diagnosis by matching patient phenotype & genotype to primary literature

AMELIE 2 improves Mendelian disorder diagnosis by matching patient phenotypes and genotypes to primary literature, achieving high accuracy and efficiency.

5’ splice site GC>GT variants differ from GT>GC variants in terms of their functionality and pathogenicity

The paper compares the functionality and pathogenicity of 5' splice site GC>GT and GT>GC variants using a meta-analysis and functional assay, finding that GC>GT variants are largely non-pathogenic.

The experimentally obtained functional impact assessments of GT>GC 5' splice site variants differ markedly from those predicted

The paper evaluates SpliceAI's performance in predicting the functional impact of GT>GC 5' splice site variants using experimental data and finds it is not fully accurate.

AVADA Enables Automated Genetic Variant Curation Directly from the Full Text Literature

AVADA automatically curates a database of pathogenic variants from full-text literature, outperforming existing methods and providing more variants than ClinVar.

Genetic analysis of the STIM1 gene in chronic pancreatitis

The paper identifies rare STIM1 coding variants enriched in chronic pancreatitis patients compared to controls, suggesting a potential genetic association.

First estimation of the scale of canonical 5’ splice site GT>GC mutations generating wild-type transcripts and their medical genetic implications

The paper estimates that 15-18% of canonical GT 5' splice sites can generate wild-type transcripts when mutated to GC, with implications for disease and splicing mechanisms.

SeqTailor: a user-friendly webserver for the extraction of DNA or protein sequences from next-generation sequencing data

SeqTailor extracts DNA or protein sequences from VCF files for genetic variant analysis, providing a user-friendly webserver to support sequence-based predictions.