Genomics and Rare Diseases

Allostery is a widespread cause of loss-of-function variant pathogenicity

The paper shows allostery is a common cause of loss-of-function variants in human genetic diseases and identifies a distance-dependent decay of mutational effects.

Using somatic data to aid germline clinical variant interpretation in developmental disorders

This paper uses somatic mutation data to improve the classification of germline variants in developmental disorders by identifying genes where somatic and germline mechanisms are concordant.

ARID1B damaging variants from more than one million genomes, cause human diseases by impairing protein-protein interactions, stability, and regulation

The paper identifies ARID1B variants that impair protein interactions, stability, and regulation, linking them to neurodevelopmental disorders and cancers.

AlphaGenome identifies a deep intronic variant in a family with PLA2G6-associated neurodegeneration: Closing the diagnostic gap in rare genetic diseases

Functional Profiling of 2,193 ASS1 Missense Variants: Insights into Variant Pathogenicity and Epistatic Interactions in Citrullinemia Type I

The paper functionally profiles 2193 ASS1 missense variants to determine their pathogenicity and epistatic interactions in Citrullinemia Type I.

Evaluating FoldX5.1 for MAVISp Stability Data Collection

This study evaluates the impact of updating FoldX from version 5 to 5.1 on MAVISp stability predictions, finding high agreement and minimal shifts in folding free energy.

Hypermutability of ultraconserved histone genes and its contribution to human disease

The paper identifies high mutation rates in histone genes due to AID/APOBEC enzymes and introduces HistMTR to predict pathogenicity, showing histone mutations contribute to diseases.

Clinical long-read genome sequencing for rare disease diagnostics

This study evaluates long-read genome sequencing in rare disease diagnostics, finding high concordance with standard-of-care tests and incremental diagnostic benefits.

Saturation Genome Editing reveals the functional impact of RAD51D and XRCC2 variants

The paper uses saturation genome editing to assess the functional impact of RAD51D and XRCC2 variants, showing high accuracy in distinguishing pathogenic from benign variants.

Long-term Penetrance of Disease Variants in Genes Prioritized for Genomic Newborn Screening: Evidence from Adult Biobanks

The paper estimates penetrance of disease variants in genes prioritized for genomic newborn screening using adult biobank data, finding higher penetrance than ICD codes suggest.

Inference of elevated mutation rates and variant effects using 700k exomes

The paper estimates mutation rates and variant effects using 700k exomes to identify genes with mutational hotspots and improve variant prioritization for genetic diagnostics.

A fine-tuned genomic language model captures nucleotide-level information overlooked by missense variant impact predictors

This study develops GLM-Missense, a genomic language model fine-tuned for missense variant impact prediction, showing it captures nucleotide-level effects missed by existing predictors.

GLOF: A large-scale expert-curated benchmark dataset of gain-of-function and loss-of-function missense variants

The paper introduces GLOF, a large-scale expert-curated dataset of missense variants classified as loss-of-function, gain-of-function, or neutral, to benchmark computational methods for predicting variant functional mechanisms.

Evidence for G6PD variant classification from multiplexed functional assays

The paper classifies G6PD variants using functional assays to identify clinically relevant variants and those unlikely to contribute to G6PD deficiency.

DeltaMut: An Integrative Database of AlphaFold2-Derived Missense Variant Structures

DeltaMut provides a large database of AlphaFold2-predicted missense variant structures to improve variant effect prediction.

Whole-exome-based preconception carrier screening in Uzbekistan with targeted SMA, FMR1, and DMD assays: the first reported clinical program

The paper reports a clinical implementation of a whole-exome sequencing-based preconception carrier screening program in Uzbekistan, identifying actionable genetic risks in couples and singletons.

MAGI: Mechanistic Consequences of Genetic Variants via Genomic Foundation Models

MAGI provides mechanistic insights into genetic variants by integrating genomic data and clinical annotations to improve variant interpretation and generate testable hypotheses.

Systematic identification of disease-associated 3D neighborhoods in protein structures

The paper develops a framework to map rare variants onto protein structures and identifies disease-associated 3D neighborhoods in 872 genes for Mendelian disease and others for autism, epilepsy, and schizophrenia.

Measuring the Meaning of Genomic Results: Harmonization of the Metric for Case-Level Results in the CSER2 Consortium

The paper develops a standardized case-level categorization metric for genomic results across the CSER2 consortium to assess diagnostic yield and identify resolvable factors in inconclusive cases.

HiFi sequencing accurately identifies clinically relevant variants in paralogous genes

This study shows that PacBio HiFi long-read sequencing with Paraphase variant caller detects all clinically relevant variants in paralogous regions, improving variant calling accuracy.

Reproducibility of the evaluation of genetic variant pathogenicity based on the animal variant classification guidelines

This study assesses the reproducibility of pathogenicity classification using the animal variant classification guidelines across three species, finding 65% reproducibility for pathogenicity and 83% clinically relevant agreement.

A Comparative Survey of Functional Evidence Use in Hearing and Vision Loss Genetics

The paper surveys genetics professionals on their use of functional evidence in variant classification for hearing and vision loss, highlighting challenges in data quality, accessibility, and integration into clinical practice.

Stratified evaluation of blood RNA sequencing in a rare disease cohort

This study evaluates RNA-seq's diagnostic utility in three patient groups with non-diagnostic exome sequencing, finding higher yields in groups with candidate variants.

Human Proteome-wide Mechanistic Interpretation of Missense Variants through Protein Feature Enrichment Score

PFES quantifies the protein context of missense variants, enabling mechanistically transparent interpretation and reclassification of variants of uncertain significance.

The Evidence Aggregator: AI reasoning applied to rare disease diagnostics

The Evidence Aggregator (EvAgg) uses generative AI to streamline rare disease diagnostics by extracting and summarizing genetic variant and clinical information from literature, improving efficiency and accuracy.

A Foundational Exome Resource for Jordan: Dual Ancestry Admixture and Population-Specific Variants to Improve Clinical Variant Interpretation

This study identifies population-specific variants in Jordanian individuals, revealing admixture patterns and reclassifying variants to improve clinical interpretation.

Structural distance at the tRNA synthetase active site interface predicts pathogenicity but is captured by AlphaMissense and EVE except among score-ambiguous variants

The paper investigates if structural distance to the tRNA-binding interface improves missense variant pathogenicity prediction, finding that existing models like AlphaMissense and EVE already capture this information.

Vision-Based Genomic Model for Copy Number Variant Pathogenicity Prediction

This paper introduces a vision-based model for predicting CNV pathogenicity using track-based spatial representations, achieving improved performance on benchmarks and clinical datasets.

Low-level mosaic variants causing the pancreatic disease congenital hyperinsulinism can be detected from blood DNA

This study detects low-level mosaic variants in blood DNA from individuals with congenital hyperinsulinism using tNGS and confirms them with ddPCR.

Deep Agentic Variant Prioritisation for Expert Level Genetic Diagnosis

DAVP uses an agentic-LLM pipeline to prioritize genetic variants for diagnosis, achieving high recall in identifying causal variants across multiple datasets.