Genomics and Rare Diseases

Expanding the mutational spectrum of GCK in Turkish pediatric population

The paper identifies 28 distinct GCK variants in 43 Turkish pediatric patients with hyperglycemia, classifying 25 as likely pathogenic and 3 as variants of uncertain significance.

Proteome-Wide Assessment of Clustering of Missense Variants in Neurodevelopmental Disorders Versus Cancer

The paper assesses clustering of missense variants in neurodevelopmental disorders and cancer, identifying proteins with significant variation patterns in each condition.

PanEffect: A pan-genome visualization tool for variant effects in maize

PanEffect visualizes variant effects across 51 maize genomes using ESM scores, enabling exploration of 550 million amino acid substitutions and 2.3 million natural variations.

RExPRT: a machine learning tool to predict pathogenicity of tandem repeat loci

RExPRT predicts pathogenicity of tandem repeat expansions with high precision, identifying ~30,000 likely pathogenic TRs in the reference genome.

PHACTboost: A Phylogeny-aware Boosting Algorithm to Compute the Pathogenicity of Missense Mutations

PHACTboost improves missense variant pathogenicity prediction by integrating phylogenetic trees, multiple sequence alignments, and ancestral reconstruction, outperforming existing tools including AlphaMissense and CPT-1.

A novel approach for simultaneous detection of structural and single-nucleotide variants based on a combination of chromosome conformation capture and exome sequencing

This paper introduces a method combining exome sequencing and chromosome conformation capture to detect both SNVs and SVs, demonstrating its effectiveness in identifying causative variants in rare disorders.

Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants

This study benchmarks AlphaMissense's ability to predict pathogenicity of CFTR missense variants using clinical and functional metrics, finding moderate correlations with some outcomes but limited utility for pharmacological response.

AutScore- An integrative scoring approach for prioritization of ultra-rare autism spectrum disorder candidate variants from whole exome sequencing data

AutScore prioritizes ultra-rare ASD candidate variants from WES data by integrating pathogenicity, clinical relevance, and inheritance patterns, outperforming existing methods in detection accuracy.

Improving estimates of negative selection in human genome using CAPS

The paper introduces CAPS, a novel metric for estimating negative selection in the human genome that improves upon MAPS by removing the mutability layer, resulting in less biased estimates and more accurate confidence intervals.

A gene pathogenicity tool 'GenePy' identifies missed biallelic diagnoses in the 100,000 Genomes Project

GenePy identifies potential missed biallelic diagnoses in the 100KGP by scoring variants and analyzing phenotypic overlaps, finding 14% of undiagnosed participants may have a missed diagnosis.

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

The paper identifies variant-specific effects of AFF3 on transcriptome profiles through analysis of patient cohorts and zebrafish models, showing distinct pathophysiological mechanisms for different types of AFF3 variants.

PrimateAI-3D outperforms AlphaMissense in real-world cohorts

The paper benchmarks PrimateAI-3D and AlphaMissense on real-world cohorts, finding PrimateAI-3D performs better in rare-disease and biobank settings.

Rare splice and missense variants with evidence of pathogenicity in consanguineous families with autosomal recessive intellectual disability from Pakistan

AXOLOTL: an accurate method for detecting aberrant gene expression in rare diseases using coexpression constraints

AXOLOTL detects aberrant gene expression in rare diseases by modeling coexpression constraints, improving causal gene prioritization in RNA-seq data.

Predicting the impact of rare variants on RNA splicing in CAGI6

The paper evaluates splicing prediction methods on 56 clinically validated variants, finding some methods match or exceed SpliceAI's performance but highlighting ongoing challenges in accuracy.

Diagnostic Yield of Exome Sequencing in a Diverse Pediatric and Prenatal Population is not Associated with Genetic Ancestry

The study finds no association between diagnostic yield of exome sequencing and genetic ancestry in a diverse pediatric and prenatal cohort.

Combined Bioinformatic and Splicing Analysis of Likely Benign Intronic and Synonymous Variants Reveals Evidence for Pathogenicity

The paper evaluates the pathogenicity of intronic and synonymous variants using splicing prediction algorithms and in vitro assays, identifying potentially disease-causing variants previously classified as benign.

Identifying Factors Important for Conservation at Sites of Synonymous Variations

The paper uses machine learning to identify factors influencing conservation at synonymous variant sites, finding that non-allele-dependent features significantly impact conservation scores.

mity: A highly sensitive mitochondrial variant analysis pipeline for whole genome sequencing data

mity detects low heteroplasmy mitochondrial variants in whole genome sequencing data, improving diagnostic rates for mitochondrial diseases.

3-hour genome sequencing and targeted analysis to rapidly assess genetic risk

This study demonstrates rapid whole-genome sequencing and targeted analysis within three hours to assess genetic risk in a newborn, showing they are not affected or a carrier for a specific Mendelian condition.

The impact of the Turkish (TK) population variome on the genomic architecture of rare disease traits

The paper analyzes the Turkish population's variome to understand its impact on rare disease traits, finding that long ROHs and inbreeding contribute to recessive diseases.

Genetic Diagnosis of Facioscapulohumeral Muscular Dystrophy Type 1 Using Rare Variant Linkage Analysis and Long Read Genome Sequencing

This study uses rare variant linkage analysis and long-read sequencing to identify a pathogenic FSHD1 allele in a family, mapping the disease locus to chromosome 4q35.2.

Evaluating the performance of protein structure prediction in detecting structural changes of pathogenic nonsynonymous single nucleotide variants

This study evaluates how well protein structure prediction tools detect structural changes caused by pathogenic nonsynonymous single nucleotide variants.

Predicting functionally important breast cancer SNPs using pleiotropy, conservation, and protein structure

The paper identifies functionally important breast cancer SNPs by analyzing pleiotropy, conservation, and protein structure to prioritize mutations likely to impact disease progression.

Whole genome and transcriptome sequencing in neuromuscular disorders: a diagnostic and health economic analysis

This paper evaluates the clinical and cost-effectiveness of combining whole-genome and RNA sequencing for diagnosing neuromuscular disorders in patients with negative whole-exome results.

Regional-specific calibration enables application of bioinformatic evidence for clinical classification of 5 prime cis-regulatory variants in Mendelian disease

The paper calibrates bioinformatic tools to classify 5' cis-regulatory variants in Mendelian disease using clinical and population datasets, finding optimal thresholds differ from coding variant standards.

Using computational approaches to enhance the interpretation of missense variants in the PAX6 gene

The paper evaluates and optimizes computational tools for predicting the pathogenicity of PAX6 missense variants, finding that AlphaMissense performs best with an optimized threshold.

A unified data infrastructure to support large-scale rare disease research

The paper describes a unified data infrastructure for rare disease research, enabling collaborative analysis of multi-omics data across institutions.

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data

The paper identifies 88 novel rare disease-gene associations using a burden analysis framework on whole genome sequencing data from the 100,000 Genomes Project, with potential clinical impact for undiagnosed cases.

Single cell sequencing as a general variant interpretation assay

The paper uses single cell RNA sequencing to assess the effects of protein-altering variants in three genes, showing that single cell expression signatures are more effective than bulk assays and computational models for predicting pathogenicity.