Undiagnosed Diseases Network

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.

Biallelic Variants in KMO Cause a Novel Form of Congenital NAD Deficiency

The paper identifies biallelic KMO variants as a novel cause of congenital NAD deficiency and shows gene x environment interactions in a mouse model.

Patient-to-patient phenotype matching enables rare disease gene prioritization beyond curated gene-phenotype associations

This paper introduces SimPheny, a framework that uses patient-to-patient phenotype matching to prioritize genes for rare disease diagnosis, outperforming existing methods in cases with limited phenotype associations.

Ensilication preserves high-molecular weight native DNA for clinical long-read sequencing

This paper demonstrates that ensilication preserves DNA integrity at ambient temperature, enabling diagnostic-quality long-read sequencing without cold-chain infrastructure.

Phenotype-Specific Recalibration of MAVE Data Enables Repurposing of BAP1 Functional Assays for Kury-Isidor Syndrome

The paper recalibrates BAP1 MAVE data for different disease phenotypes to enable accurate variant classification across related disorders.

VUStruct: a compute pipeline for high throughput and personalized structural biology

VUStruct analyzes genetic variants of unknown significance by integrating 3D protein structure data and machine learning to improve clinical and research interpretation of rare genetic disorders.

Genome-wide detection and clinical prioritization of tandem repeat outliers using long-read sequencing

The paper develops TRoLR, a pipeline using long-read sequencing to detect and prioritize pathogenic tandem repeat expansions in diverse populations, identifying known and novel expansions with clinical relevance.

Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder

The paper identifies biallelic variants in RNU2-2 as a common cause of recessive neurodevelopmental disorders, showing higher prevalence than the dominant form in England.

An optimized variant prioritization process for rare disease diagnostics: recommendations for Exomiser and Genomiser

This paper optimizes variant prioritization parameters for Exomiser and Genomiser to improve diagnostic yield in rare disease cases using WES and WGS data.

The Utility of Ultra-Deep RNA sequencing in Mendelian Disorder Diagnostics

This study evaluates ultra-high-depth RNA-seq for Mendelian disorder diagnostics, showing improved detection of low-abundance transcripts and splicing variants, and introduces a resource to guide sequencing depth selection.

Heterozygous variants in PLCG1 affect hearing, vision, cardiac, and immune function

The paper reports seven individuals with PLCG1 variants causing hearing, vision, cardiac, and immune issues, and shows these variants have gain-of-function effects in Drosophila models.

Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders

This study identifies de novo ATP5F1A variants causing neurological disorders through dominant negative mechanisms, expanding the known phenotypic and genotypic spectrum of complex V deficiency.

Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations

The paper presents a joint genomic analysis of UDN patients using whole genome sequencing and new statistical methods to prioritize disease genes, revealing new disease associations and releasing a software tool for cohort analysis.

Complexome profiling showed impaired immunoproteasome assembly in a novel PRAAS subtype caused by monoallelic PSMB8 variants

The paper identifies monoallelic PSMB8 variants causing impaired immunoproteasome assembly and a novel PRAAS subtype with immunodeficiency.

Few shot learning for phenotype-driven diagnosis of patients with rare genetic diseases

SHEPHERD uses few-shot learning and a knowledge graph to improve diagnosis of rare genetic diseases using simulated data and real-world patient cohorts.

Integration of transcriptomics and long-read genomics prioritizes structural variants in rare disease

The paper integrates long-read sequencing and gene expression to prioritize functional structural variants and tandem repeats in rare disease patients, identifying potential causal variants in a neurodevelopmental disorder.

De novo variants in KDM2A cause a syndromic neurodevelopmental disorder

This study identifies de novo KDM2A variants as a cause of a syndromic neurodevelopmental disorder with specific clinical features and functional consequences.

Clinical validation of RNA sequencing for Mendelian disorder diagnostics

This study validates a clinical RNA-seq test for diagnosing Mendelian disorders using 150 samples, achieving over 99% sensitivity and specificity.

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.

Resolution of SLC6A1 variable expressivity in a multi-generational family using deep clinical phenotyping and Drosophila models

The paper identifies a hypomorphic SLC6A1 variant causing variable expressivity in neurodevelopmental disorders using clinical phenotyping and Drosophila models.

Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature

This study evaluates genome-wide DNA methylation analysis in genetically unsolved DEEs, identifying 10 causative or candidate genetic causes and refining a CHD2 episignature.

Impact of genome build on RNA-seq interpretation and diagnostics

This study examines how different genome builds affect RNA-seq results in rare disease samples and recommends cross-referencing with a database of build-dependent genes for more accurate transcriptomics analysis.

TUBB4B variants specifically impact ciliary function, causing a ciliopathic spectrum

The paper identifies TUBB4B mutations causing distinct ciliopathic diseases by affecting microtubule dynamics and cilia formation in humans and mice.

Mind the gap: the relevance of the genome reference to resolve rare and pathogenic inversions

The paper investigates how different genome references affect inversion detection, showing that T2T-CHM13 and long-read sequencing improve resolution of challenging inversions.

VarPPUD: Variant post prioritization developed for undiagnosed genetic disorders

VarPPUD improves the prioritization of pathogenic variants in undiagnosed genetic disorders by distinguishing likely from unlikely disease-causing variants using machine learning.

Loss of function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly

The paper identifies de novo RBBP5 variants in individuals with neurodevelopmental disorders and shows they cause loss of function through structural and Drosophila model analyses.

Novel syndromic neurodevelopmental disorder caused by de novo deletion of CHASERR, a long noncoding RNA

The paper identifies a novel neurodevelopmental disorder caused by de novo deletion of the lncRNA CHASERR, showing its role in regulating CHD2 expression and causing developmental and epileptic encephalopathy.

Simulation of undiagnosed patients with novel genetic conditions

This paper simulates patients with novel genetic conditions to evaluate gene prioritization methods in diagnosing rare disorders.

A de novo missense variant in EZH1 associated with developmental delay exhibits functional deficits in Drosophila melanogaster

A de novo EZH1 variant p.Ala678Gly is linked to neurodevelopmental delay and shows functional deficits in Drosophila melanogaster.