Genomics and Rare Diseases

Genomic heterogeneity inflates the performance of variant pathogenicity predictions

The paper evaluates AI models for predicting pathogenic variants, finding that performance is inflated by genomic heterogeneity in pathogenic variant prevalence.

ESMRank reveals a transferable axis of protein mutational constraint from overlapping variant effect assays

ESMRank is a sequence-based predictor that integrates protein language models and physicochemical features to rank mutational constraint across proteins, outperforming existing methods and capturing disease-relevant variants.

Cardiologists perspectives on sociocultural and structural factors shaping cardiovascular genetic testing

This study explores how sociocultural and structural factors influence cardiovascular genetic testing practices among cardiologists.

Using SpliceAI to triage splice-altering variants in 7,220 individuals with rare conditions highlights limitations of the precomputed scores

The paper evaluates precomputed SpliceAI scores for splice-altering variant prioritization in NDD cohorts, finding inaccuracies and providing a tool to improve variant triage.

MetaDome 2027: a comprehensively updated resource for aggregating missense variant evidence across homologous human protein domains

MetaDome now supports GRCh38 alongside GRCh37, adds coordinate lookup, and identifies 52,463 GRCh38 ClinVar missense variants of uncertain significance with uncontradicted pathogenic evidence at homologous Pfam-domain positions.

Long-read sequencing with targeted assembly of the opsin locus accurately evaluates genes in expressed positions

This paper evaluates long-read sequencing with targeted assembly for accurately analyzing the opsin gene cluster, showing high concordance and improved detection of color vision deficiencies and carrier status.

The prevalence of protein misfolding as a mechanism for hereditary deafness

The paper evaluates computational frameworks to prioritize pathogenic variants in deafness-associated genes, identifying 28,866 VUSs with high pathogenicity probability and improving diagnoses for 12 patients.

MaveMD: A functional data resource for genomic medicine

MaveMD provides a clinical interface for MAVE data to classify variants of uncertain significance and improve genetic medicine outcomes.

Automated GenePy Gene-Burden Computation via a Reproducible Nextflow Workflow Integrated with the Genomics England (GEL) Lifebit Platform

GenePy computes gene-level burden scores using variant data to improve diagnostic strategies for rare diseases through automated, scalable workflows.

RAPID: A Targeted Long-Read RNA Workflow for Functional Resolution of Splicing Variants in Rare Disease

RAPID uses targeted long-read RNA sequencing to resolve splice variants in rare disease cases, providing functional evidence for diagnosis and variant interpretation.

Functional screening of ZIP8 naturally occurring variants identifies pathogenic mutations and trafficking defects

The paper functionally screens ZIP8 variants to identify pathogenic mutations and trafficking defects using a combined experimental and computational approach.

MissenseHMM: state-based annotations for missense variants through joint modeling of pathogenicity scores

MissenseHMM annotates missense variants with states derived from joint modeling of pathogenicity scores, improving associations with clinical and experimental data.

Exploring the feasibility, acceptability and impact of genomic newborn screening for rare diseases in England: A study protocol for the Generation Study - Process and Impact Evaluation

Comprehensive analysis of non-synonymous single-nucleotide polymorphism of human TSC1 and TSC2 genes: an in silico approach.

This study identifies high-risk nsSNPs in TSC1 and TSC2 genes using computational tools, showing they reduce protein stability and disrupt functional sites.

Equity in genome sequencing for rare disease diagnosis: a cross-sectional analysis of data from the UK 100,000 Genomes Project

This study examines ancestry-related differences in variant prioritisation and diagnostic outcomes in the UK 100,000 Genomes Project, finding disparities in positive predictive value and variant of uncertain significance frequencies across groups.

LDLR variant classification through activity-normalized prime editing screening

This paper uses prime editing to classify LDLR variants by measuring their impact on LDL-C uptake, reclassifying many previously unclassified variants.

Mutation timing, accumulation and selection in the male germline shape inheritance risk for developmental disorders

The paper investigates how mutation timing, accumulation, and selection in the male germline influence the risk of developmental disorders through de novo mutations.

T-Rex: Standardized Analysis of Germline Variants in Whole-Exome Sequencing Trios

T-Rex provides a standardized, no-programming-required tool for analyzing whole-exome sequencing trio data, achieving high precision and sensitivity in variant calling and filtering.

aiDIVA - Diagnostics of Rare Genetic Diseases Using Large Language Models

aiDIVA uses AI and LLMs to prioritize causal genetic variants in rare diseases, achieving high accuracy in identifying top candidates.

Genomize-SEQ: An NGS data analysis platform for genomic variant classification and prioritization

Genomize-SEQ is a web-based platform for genomic variant classification and prioritization, achieving high accuracy in identifying causative variants for rare diseases.

Why variant effect predictors and multiplexed assays agree and disagree

The paper compares variant effect predictors and MAVEs to understand their agreement and disagreement in assessing genetic variant impacts.

Long-read transcriptome analysis using IsoRanker for identifying pathogenic variants in Mendelian conditions

IsoRanker uses long-read transcriptomics to prioritize non-coding variants in Mendelian conditions by detecting expression outliers, allelic imbalance, and NMD, leading to the identification of pathogenic variants in one individual.

Ancestry-stratified variant classification in monogenic diabetes genes: annotation coverage and differential curation burden

The paper evaluates variant classification disparities in monogenic diabetes genes across ancestry groups using ClinVar and gnomAD, finding significant annotation gaps and curation biases in non-European populations.

Dynamics-aware Evolutionary Profiling Uncouples Structural Rigidity from Functional Motion to Enable Enhanced Variant Interpretation

This paper introduces Dynamics-Aware Evolutionary Profiling to separate structural rigidity from functional motion in proteins, improving variant interpretation by identifying dynamic-conserved residues.

Shared inheritance reveals landscape of somatic and germline cancer risk in TP53

The paper distinguishes germline and somatic TP53 variants using whole-exome data from UK Biobank participants, showing somatic variants dominate cancer risk in middle-aged adults.

A structure and function-based complete mutational map of Human Hemoglobin using AI

The paper develops a pathogenicity prediction model for hemoglobin variants using structure-informed features and ML, showing strong performance compared to AlphaMissense and providing a complete mutational landscape for HbA.

DAVE: how to use explainable AI to interpret missense variants for genome diagnostics based on functional protein modeling

DAVE uses explainable AI to interpret missense variants by integrating biophysically grounded features, improving variant classification and interpretability for genome diagnostics.

Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project

This study uses long-read sequencing to identify pathogenic structural variants in undiagnosed rare disease families, increasing diagnostic yield in three families.

Variant characterization in the intrinsically disordered human proteome

The paper improves variant effect prediction in intrinsically disordered regions by combining sequence analysis, AlphaFold, and experiments to annotate protein interactions and predict deleterious variants.

Sequence effects on mutation frequencies investigated in whole-genome sequenced UK Biobank participants

The paper analyzes mutation frequencies in UK Biobank whole-genome sequences, finding that AC25 variants closely match de novo mutations and are influenced by DNA context and transcriptional processes.