Genomics and Rare Diseases

Recalculated CNV penetrance: what it does and does not change for counselling

The paper recalculates CNV penetrance for intellectual disability, showing lower estimates due to methodological differences, and recommends phenotype-specific risk reporting.

Long-read sequencing and benchmarking of saliva against blood for genomic variant detection in autism

This study benchmarks saliva-derived DNA against blood for long-read sequencing in autism, showing comparable variant detection despite nonhuman DNA contamination.

Proximity-mapped whole-genome sequencing for characterization of repeat expansions and variants in highly homologous genomic regions

This study evaluates TruPath Genome's ability to characterize repeat expansions and variants in complex genomic regions using archived DNA samples, showing consistent results with orthogonal methods.

A national ecosystem for long-read genome sequencing: Integrating population genomics and rare disease diagnostics in Sweden

This paper evaluates the clinical use of long-read genome sequencing in Sweden, showing it provides molecular diagnoses and reduces diagnostic costs.

Gene-level evolutionary conservation and human constraint decline at comparable rates across the age of onset of Mendelian disease

The paper compares the rate of decline in gene-level evolutionary conservation and human constraint scores with disease onset age across Mendelian diseases.

Unveiling the Hidden Rules: Enhancing NMD Prediction for Protein-Truncating Variants

The paper develops a model to predict NMD outcomes for protein-truncating variants using RNA-seq data, achieving ~78% ROC-AUC and identifying non-canonical determinants.

Systematic evaluation of incomplete penetrance in 4,325 rare disease families reveals divergent transcriptional networks in CHD8 pathology

The paper evaluates incomplete penetrance in 4,325 rare disease families, finding 1.6% of diagnosed cases involve inherited variants from unaffected parents and showing divergent transcriptional effects in CHD8-related cases.

Overcoming a diagnostic blindspot: Identifying balanced translocations in Mendelian rare disease cohorts

This paper develops a specific pipeline to detect balanced reciprocal translocations in genomic data and applies it across multiple cohorts to assess their prevalence and diagnostic impact.

Molecular Diagnosis as a Probability of Necessity

The paper introduces the Probability of Necessity (PN) to assess genetic diagnosis, showing it differs from penetrance and can resolve variant classification ambiguity in diseases like ischemic heart disease and Parkinson's.

Disease-associated protein states accessible to 8-oxoguanine transcriptional miscoding without genomic mutation

The paper identifies disease-associated protein states caused by 8-oxoG transcriptional miscoding, showing 5.7% of pathogenic missense variants can arise without genomic mutation.

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.

Phenotypes of ultra-rare variant carriers benchmark variant effect scores

The paper benchmarks variant effect scores using UK Biobank data on ultra-rare variant carriers, showing coding and splicing scores better predict protein abundance and traits than transcriptional regulation models.

Functional modelling of human infertility-associated genetic variants using C. elegans and mice

This study uses C. elegans and mouse models to functionally validate infertility-associated genetic variants in MSH4, showing their pathogenic effects on meiotic processes in both sexes.

Applying AlphaGenome Variant Impact for SNV Prioritization

The paper establishes AVI_QUANTILE thresholds for classifying SNVs using ClinVar data and evaluates their performance in variant prioritization and fine-mapping.

Scalable saturation mutagenesis reveals gene regulatory architecture and rare variant effects

The paper introduces Multi-ISM, a scalable framework for saturation mutagenesis that reduces computational cost while maintaining accuracy, and applies it to 5,000 genes to map regulatory elements and rare variant effects.

SysNDD: A Systematic Database for Neurodevelopmental Disorders

SysNDD is a curated database of gene-disease associations for neurodevelopmental disorders, providing standardized evidence and annotations for 4,275 entities from 4,932 publications.

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.

Integrated Clinical-Genomic Reanalysis Identifies Diagnostic Gaps and Candidate Genes in a Pediatric Rare Disease Cohort

A refined sticker-spacer grammar marks disordered regions with interpretable pathogenic missense variation

The paper identifies a refined sticker-spacer grammar in phase-separating IDRs that correlates with pathogenic missense variants and explains mutational vulnerability in disordered proteins.

Comprehensive in silico analysis reveals candidate regulatory mechanisms underlying selective cerebellar vulnerability in pontocerebellar hypoplasia

This study identifies candidate regulatory mechanisms for cerebellar vulnerability in PCH by analyzing variant effects and gene expression patterns.

Evolving clinical roles in the era of genomic medicine: Insights from rapid genome sequencing in the neonatal intensive care unit

The paper examines challenges in clinical roles during rapid genome sequencing in NICUs, identifying ambiguities in subspecialist consultations and responsibilities.

Single-cell profiling resolves gain- and loss-of-function mechanisms in CASR to advance mechanism-aware variant classification

The paper uses single-cell RNA-seq and machine learning to classify CASR variants as gain- or loss-of-function, achieving high accuracy and clinical validation.

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.

vep-rs: high-throughput Rust variant annotation with population-scale concordance to Ensembl VEP

vep-rs is a Rust reimplementation of Ensembl VEP with high concordance and significantly improved throughput for variant annotation.

A stepwise short- and long-read whole genome sequencing strategy resolves previous genetically unresolved inherited retinal disease cases

This paper reanalyzes short-read WGS data and applies long-read WGS to improve genetic diagnosis of inherited retinal disease cases that were previously unresolved.

Mechanism-selective deep mutational scanning distinguishes ERCC2 disease phenotypes

The paper uses deep mutational scanning to distinguish disease mechanisms in ERCC2 variants, finding that TTD variants have lower fitness than XP variants.

nf-rare-var-assoc: a comprehensive genetic association pipeline with rich QC

The paper presents a Nextflow-based pipeline for genetic association analysis of exome sequencing data, designed to simplify and standardize the process for small cohorts.

MutCleaner: Cleaning and Standardizing Biological Mutation Datasets for Variant Effect Prediction

MutCleaner standardizes mutation datasets for variant effect prediction by cleaning, validating, and organizing mutation records across 16 datasets with over 12.14 million entries.

AlphaGenome Atlas: in silico mutagenesis of the entire human genome improves prioritization and interpretation of non-coding variants

AlphaGenome Atlas predicts regulatory effects of non-coding variants across the human genome, improving their prioritization and interpretation.

Identifying Putative Pathogenic Non-Coding Variants in Unresolved Rare Disease Patients Using Topologically Associated Domains

The paper introduces GAVURD, a system to identify putative pathogenic non-coding variants in unresolved rare disease patients using trio whole genome sequencing and TAD data, and identifies six potentially causal variants in ten probands.