Genomics and Rare Diseases

SeqFirst: Building equity access to a precise genetic diagnosis in critically ill newborns

SeqFirst-neo uses a genotype-driven workflow with broad exclusion criteria to increase access to rapid whole genome sequencing in critically ill newborns, significantly improving the rate and equity of precise genetic diagnoses.

Automating ACMG Variant Classifications With BIAS-2015 v2.0.0: Algorithm Analysis and Benchmark Against the FDA-Approved eRepo Dataset

BIAS-2015 v2.0.0 automates ACMG variant classification, outperforming InterVar in sensitivity and speed using the FDA-approved eRepo dataset.

NAVIP: Unraveling the Influence of Neighboring Small Sequence Variants on Functional Impact Prediction

NAVIP predicts the functional impact of sequence variants by considering neighboring variants, improving accuracy over single-variant tools like SnpEff.

Using The Cancer Genome Atlas from cBioPortal to Develop Genomic Datasets for Machine Learning Assisted Cancer Treatment

The paper develops genomic and non-genomic datasets from TCGA to predict PolyPhen and SIFT scores using machine learning models, finding genomic data provides more accurate predictions.

Genome-Wide Analysis Reveals a Role of 3'untranslated Region Variants Affecting Cleavage and Polyadenylation in Undiagnosed Rare Disorders

The paper identifies 3'UTR variants disrupting cleavage and polyadenylation as potential causes of undiagnosed rare disorders using deep learning on Genomics England data.

Endogamy and high prevalence of deleterious mutations in India: evidence from strong founder events

The paper analyzes whole-exome sequencing data from South Indian populations to identify founder events and deleterious mutations, revealing high inbreeding rates and population-specific pathogenic variants.

Leveraging next-generation phenotyping for ACMG classification from VUS to likely pathogenic in Mowat-Wilson syndrome

The paper reclassifies a variant of uncertain significance as likely pathogenic in Mowat-Wilson syndrome using next-generation phenotyping and multimodal data integration.

Long-read sequencing resolves the clinically relevant CYP21A2 locus, supporting a new clinical test for Congenital Adrenal Hyperplasia

This paper uses long-read sequencing to comprehensively identify pathogenic variants in the CYP21A2 locus for Congenital Adrenal Hyperplasia, including phasing and module counts, improving diagnostic accuracy.

The impact of systematized generation, evaluation, and incorporation of machine learning algorithms for clinical variant classification

The paper develops a machine learning platform to improve variant classification, reducing VUS rates and improving concordance with ClinVar submissions.

ESM-Effect: An Effective and Efficient Fine-Tuning Framework towards accurate prediction of Mutation's Functional Effect

ESM-Effect is a fine-tuning framework for predicting mutation functional effects, achieving state-of-the-art performance and faster training than multi-modal methods.

MAJIQ-CLIN: A novel tool for the identification of Mendelian disease-causing variants from RNA-Seq data

MAJIQ-CLIN improves the detection of Mendelian disease-causing variants from RNA-Seq by addressing splicing aberrations, showing better accuracy and efficiency than existing tools.

Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition

Pooling Fiber-seq gDNA with concatenated MAS-Seq cDNA in one PacBio run gives phased genome, methylome, chromatin, and transcriptome, exposing four gene disruptions from one X;13 translocation.

The spectrum of gene intolerance to variation: Insights from a rare disease cohort

The paper analyzes gene intolerance to loss-of-function variation in a rare disease cohort to identify patterns in gene expression, sequence features, and disease associations across FUSIL categories.

A de novo variant in PAK2 detected in an individual with Knobloch type 2 syndrome

The paper identifies a novel de novo PAK2 variant in a patient with Knobloch syndrome type 2, supporting PAK2's role in the disorder and expanding its clinical features.

Comparative evaluation of four exome enrichment solutions in 2024: Agilent, Roche, Vazyme and Nanodigmbio

This study compares four exome enrichment kits, finding high coverage and variant calling accuracy, with Nanodigmbio showing highest precision and Vazyme and Nanodigmbio comparable to Agilent and Roche.

Insights on improving accessibility and usability of functional data to unlock its potential for variant interpretation

This study identifies barriers to using functional data in clinical variant interpretation and highlights the need for better access and standardized interpretation guidelines.

Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection

This study evaluates the diagnostic yield of long-read nanopore sequencing in rare disease detection, finding it covers more genes and detects additional variants compared to short-read sequencing.

Mutation hot spots for clinical pathogenicity across the SLC6 transporter family

The paper identifies mutation hotspots in SLC6 transporters linked to clinical pathogenicity by analyzing protein-protein interactions and structural data.

Functional impact of rare variants and sex across the X-chromosome and autosomes

The paper investigates functional rare variants on the X-chromosome and autosomes, showing sex-biased effects and pharmacogenomic implications.

AFFIPred: AlphaFold2 Structure-based Functional Impact Prediction of Missense Variations

AFFIPred uses AlphaFold2 structures and machine learning to predict the pathogenicity of missense variants, achieving performance comparable to existing methods without relying on experimental structures.

Polycomb-associated and Trithorax-associated developmental conditions - phenotypic convergence and heterogeneity

The paper analyzes phenotypic similarities and differences in developmental conditions caused by rare variants in PcG and TrxG genes using data-driven methods, revealing phenotypic convergence and heterogeneity.

HiFi long-read genomes for difficult-to-detect clinically relevant variants

The paper demonstrates that HiFi long-read sequencing can detect 93% of clinically relevant variants challenging to identify with short-read sequencing, using 30x coverage and showing potential for cost-effective diagnostic implementation.

Enhancing the annotation of small ORF-altering variants using MORFEE: introducing MORFEEdb, a comprehensive catalog of SNVs affecting upstream ORFs in human 5'UTRs

The paper introduces MORFEE, a tool to identify SNVs altering small ORFs in human transcripts, and presents MORFEEdb, a catalog of such variants, showing over 45% of UTR-SNVs can affect upORFs or dORFs.

protPheMut: An Interpretable Machine Learning Tool for Classification of Cancer and Neurodevelopmental Disorders in Human Missense Variants

protPheMut predicts cancer and neurodevelopmental disorder phenotypes from missense variants using interpretable machine learning, achieving high accuracy in PI3K and PTEN mutation analysis.

Population-scale variability at short tandem repeat loci reveals pathogenicity signature

The paper uses long-read sequencing data to analyze STR variability across 2,645 individuals, identifying disease-associated STR loci with elevated allelic variability and introducing the PLVI metric.

GPN-MSA: an alignment-based DNA language model for genome-wide variant effect prediction

GPN-MSA is a DNA language model that predicts variant effects across the human genome using whole-genome alignments, achieving strong performance on deleteriousness prediction for coding and non-coding variants.

Complementary roles of structure and variant effect predictors in RyR1 clinical interpretation

This study evaluates 70 variant effect predictors for RyR1 missense variants and introduces a structural metric, SPDV, to assign ACMG/AMP evidence levels for clinical interpretation.

NeuroTri2-VISDOT: An open-access tool to harness the power of second trimester human single cell data to inform models of Mendelian neurodevelopmental disorders

NeuroTri2-VISDOT provides a web-based tool to explore second trimester human single-cell RNA sequencing data for Mendelian neurodevelopmental disorders, aiding in model system selection.

The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease Relationships

The paper curates 111 gene-disease relationships for syndromic disorders, classifying their clinical validity and identifying gaps in knowledge.

Adaptation of ACMG/AMP guidelines for clinical classification of BMPR2 variants in Pulmonary Arterial Hypertension resolves variants of unclear pathogenicity in ClinVar.

The paper develops adapted ACMG/AMP guidelines for classifying BMPR2 variants in PAH, resolving 66% of uncertain variants as benign or likely benign.