Genomics and Rare Diseases

TrioNsight: Building a meta-predictor to evaluate the clinical impact of TrioN-like Dbl-homology domain variants

TrioNsight is a meta-predictor that evaluates the clinical impact of TrioN-like Dbl-homology domain variants using structural, evolutionary, and physiochemical features.

Genetic Counselor Utilization Across Non-Genetics Departments for Neurodevelopmental Disorders

This study surveys non-genetics departments to assess genetic counselor availability, utilization, and perceived need for neurodevelopmental disorder patients, finding limited integration but high interest in expanding genetic counseling support.

NFIX missense variants that disrupt the β-hairpin loop result in a severe form of Malan syndrome in adolescence with rapidly evolving scoliosis and muscle wasting

The paper identifies severe NFIX missense variants causing a subtype of Malan syndrome with progressive musculoskeletal issues and shows variant-specific DNA-binding disruptions.

Expanding the Clinical and Molecular Spectrum of TUBB2B Through Distinct Variants Identified Across Multiple Families

The paper reports new TUBB2B variants in multiple families, expanding the clinical and molecular spectrum of tubulinopathies and highlighting phenotypic heterogeneity and dual molecular diagnoses.

Cancer Variant Interpretation Group UK (CanVIG-UK): updates on an exemplar national subspecialty multidisciplinary network

CanVIG-UK evaluates the impact of its activities on variant interpretation in cancer susceptibility genes through a survey, showing high utility and usage of its consensus recommendations.

Phenotype Dependent Segregation of a Novel EPS8 Variant for Hearing Loss and an HPDL Variant for Neurodevelopmental Disorders in a Complex Consanguineous Family

The paper identifies two pathogenic variants in a consanguineous family, one causing hearing loss and the other neurodevelopmental disorder, through genomic and transcriptomic analysis.

Dissecting the functional landscape of rare diseases through genomic variation in a heterogeneous cohort of 11,000 patients

This study uses genomic data from 11,084 patients to build a variant database and identify disease-associated signals, leading to molecular diagnoses in 32 unsolved rare disease cases.

Clinical validation of large-scale functional assays: insights from 2,120 gene-truthset-assay evaluations

The paper evaluates how different truthset strategies affect evidence points (EPs) in clinical validation of functional assays across 2,120 gene-truthset-assay combinations.

'Truthsets' for clinical validation of large-scale functional assays: Practice recommendations from Cancer Variant Interpretation Group UK (CanVIG-UK)

The paper establishes consensus guidelines for constructing truthsets to validate functional assays in cancer variant interpretation, focusing on missense variants and clinical validation frameworks.

Clinical Evaluation of an AI System for Streamlined Variant Interpretation in Genetic Testing

DiagAI, a machine-learning system, improves variant interpretation in genetic testing by prioritizing causal variants, outperforming existing tools with higher diagnostic yield and shorter variant shortlists.

Interpretable variant effect prediction from genomic foundation model embeddings

A low-rank covariance probe on Evo 2 embeddings predicts ClinVar pathogenicity across SNVs and indels, while annotation probes plus an LLM produce mechanistic hypotheses; scores released for 4.2 million variants.

Benchmarking long-read variant sensitivity across ONT and PacBio platforms using known clinically reported variants in a cohort of critically ill newborns

MARiO: predicting cancer variant pathogenicity by integrating in silico evaluation and patient-level mutational contexts

MARiO predicts cancer missense variant pathogenicity by integrating variant-level features and patient-level clinical and genomic contexts, achieving high accuracy.

Evaluating the cross-species transferability and scaling of sequence-to-function predictions in AlphaGenome

The paper evaluates AlphaGenome's cross-species performance on mouse data, showing varying accuracy for different functional tasks and introduces a confidence scoring method for AI predictions.

Coordinate- and Sequence-Based Features for a new Combined Annotation-Dependent Depletion Framework of Structural Variants (CADD-SV v2.0)

CADD-SV v2.0 improves variant prioritization by integrating coordinate- and sequence-based features, outperforming previous versions and other tools for structural variant deleteriousness scoring.

Low-cost rare variant detection for population scale genetic screening

This paper introduces DoBSeq, a low-cost framework for detecting rare variants in population-scale genetic screening, achieving 95% variant detection and recovering all clinically relevant pathogenic variants in ACMG genes.

Copy Number Variant analysis by exome sequencing is an effective approach to optimize diagnostic yield for developmental disorders, the DDD-Africa study

The paper demonstrates that integrating CNV detection into exome sequencing analysis improves diagnostic yield for developmental disorders in the DDD-Africa cohort by 8.3% without additional costs.

FIND: a software tool for identifying population-enriched pathogenic variants in gnomAD

FIND identifies population-enriched pathogenic variants in gnomAD by comparing frequencies across ancestry groups, revealing known and novel variants in specific populations.

Characterization of Leukodystrophy Penetrance Using Large-Scale Integration of Genomic Population Screening and Electronic Health Records

The paper integrates genomic screening with EHR data to assess leukodystrophy penetrance and phenotypic variability, finding reduced penetrance and broad phenotypic spectra in some cases.

criTRia: A Classification System and Evidence Criteria for Tandem Repeat Locus-Disease Relationships

The paper introduces criTRia, a framework to evaluate TR locus-disease relationships, curating 65 loci and identifying inconsistencies in existing gene-level classifications.

Benchmarking large language models for ACMG/AMP variant interpretation and variant calling

This paper benchmarks large language models for variant interpretation and calling by evaluating safety, validity, and reproducibility rather than accuracy alone.

Saturation-seq integrates single-cell saturation genome editing and RNA-seq to quantify NFE2L2 (NRF2) variant effects

Saturation-seq combines genome editing and single-cell RNA-seq to quantify variant effects on NFE2L2, accurately distinguishing pathogenic from benign variants.

Elective genomic sequencing for adults in research, clinical and commercial contexts

The paper examines motivations and outcomes of elective genomic sequencing across research, clinical, and commercial contexts, finding most participants found results medically important but few shared them with healthcare providers.

WxS-QC - a quality control pipeline for human Whole-Genome and Whole Exome sequencing cohorts

The paper introduces WxS-QC, a quality control pipeline for human WGS and WES data, and provides an open test dataset to evaluate QC methods.

Systematic analysis of homozygous autosomal copy number losses in exomes improves diagnostic yield and uncovers ultra-rare recessive disorders

The paper systematically analyzes homozygous autosomal copy number losses in exomes to improve diagnostic yield and identify ultra-rare recessive disorders.

Cell type-specific contextualisation of the human phenome: towards the systematic treatment of all rare diseases

The paper systematically identifies cell type-specific mechanisms for 86.7% of rare disease phenotypes using transcriptomic data and the Human Phenotype Ontology, with results accessible via an interactive web portal.

Structural variant discovery and diagnostic impact in rare diseases from short-read and long-read sequencing

This study evaluates the diagnostic yield of short-read and long-read sequencing in rare diseases, finding limited added value from long-read sequencing despite increased variant discovery.

Defining the molecular tolerance-to-damage landscape of SMARCA4 helicase genetic alterations

This study develops a helicase-specific variant effect predictor to classify SMARCA4 variants as damaging or tolerated, improving interpretation of genetic variants of uncertain significance.

predNMD: prediction of nonsense-mediated mRNA decay for improved clinical variant pathogenicity classification

predNMD improves clinical variant pathogenicity classification by predicting nonsense-mediated mRNA decay (NMD) more accurately than the 50nt rule, using a random forest model trained on diverse datasets.

Functional Effect Predictions For Ion Channel Missense Variants Using a Protein Language Model

The paper introduces MissION, a protein language model-based classifier for predicting functional effects of ion channel missense variants, achieving higher accuracy than existing models.