Joseph G. Gleeson

SNX13 and SNX14 interorganelle tethers suppress lysosome membrane damage and neurodegeneration

This study identifies SNX13 and SNX14 as proteins that maintain lysosome membrane integrity and prevent neurodegeneration by supporting lipid homeostasis and repair mechanisms.

Haploinsufficiency, de novo and biallelic missense variants in CSMD2 are associated with neurodevelopmental disorders

The paper identifies rare variants in CSMD2 associated with neurodevelopmental disorders, showing both recessive and dominant inheritance patterns and functional impairments.

Benchmarked sequencing methods reveal hidden mosaic variation in the human brain

The paper benchmarks sequencing methods to recover mosaic variants in human brain tissue and introduces RIVER to enhance variant detection across methods.

Truncated ASXL3 Alters Chromatin Accessibility and Epigenetic Landscape in Bainbridge-Ropers Syndrome Suggesting a Gain-of-Function Etiology

Patient-derived neuronal models and mouse models reveal that truncated ASXL3 drive epigenetic dysregulation through a gain-of-function mechanism.

ASXL3 truncating patient variants mediate transcriptional gain-of-function and are antisense oligonucleotide-responsive

The paper shows ASXL3 truncating variants cause disease via gain-of-function, not loss-of-function, and demonstrates antisense oligonucleotides can reverse the transcriptional effects.

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.

Genomic mosaicism reveals developmental organization of trunk neural crest-derived ganglia

The paper uses genomic mosaicism to study clonal dynamics of trunk neural crest-derived ganglia, finding conserved developmental patterns across species.

Scaling haplospecific antisense oligonucleotides from N-of-1 to broad use in genetic disease populations by diplotyping

The paper identifies haplospecific antisense oligonucleotides for genetic disorder treatment using population genome sequencing and haplotyping.

MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy

This study identifies homozygous loss-of-function MDGA2 variants in individuals with developmental and epileptic encephalopathy, establishing MDGA2 as a novel gene for this condition.

Direct identification of de novo mobile element insertions from single molecule sequencing of human sperm

The paper directly identifies de novo mobile element insertions in human sperm using long-read sequencing and finds age-related increases in retrotransposition rates.

A Universal Duplex Sequencing Approach for Accurate Detection of Somatic Mutations

This paper introduces UDSeq, a duplex sequencing protocol for accurate somatic mutation detection with low DNA input and high coverage, achieving a low error rate and enabling cross-species profiling.

A phenotypic brain organoid atlas for neurodevelopmental disorders

The paper presents a brain organoid atlas of 352 patient-derived iPSCs from neurodevelopmental disorders, showing disease-specific cellular defects in organoids.

Biallelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a syndromic neurodevelopmental disorder

This study identifies biallelic TRMT1 variants causing a syndromic neurodevelopmental disorder through tRNA modification defects in humans and zebrafish.

Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases

The paper identifies mitochondrial DNA variants in undiagnosed rare disease families using exome and genome sequencing data, leading to diagnoses in 0.4% of cases.

Saturation genome editing of RNU4-2 reveals distinct dominant and recessive neurodevelopmental disorders

This study uses saturation genome editing to analyze RNU4-2 variants, identifying functional impacts and redefining the ReNU syndrome critical region.

The contribution of de novo coding mutations to meningomyelocele

The paper identifies de novo mutations contributing to meningomyelocele risk by analyzing trios and finding damaging mutations in 22.3% of cases.

Genotypic and phenotypic analysis of 173 patients with extremely rare pathogenic mutations who applied for experimental antisense oligonucleotide treatment

The paper analyzes genotypic and phenotypic data from 173 patients with nano-rare mutations to explore genotype-phenotype relationships and the potential for antisense oligonucleotide therapy.

Cell-type-resolved somatic mosaicism reveals clonal dynamics of the human forebrain

The paper uses mosaic variant barcodes to analyze clonal dynamics in human forebrain cell types, revealing lineage relationships and clonal spread patterns.

Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease

The paper detects and classifies copy number variants in exome data from 6,633 families, identifying causal CNVs in 173 families and improving classification standards.

Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis

This study evaluates genome sequencing's diagnostic yield in a cohort of undiagnosed rare disease patients, finding it solves 29.3% of cases with specific variant types not detectable by exome sequencing.

Biallelic loss of function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental delay syndrome

This study identifies biallelic loss-of-function variants in WBP4 as a cause of a neurodevelopmental syndrome with variable manifestations.

Comprehensive multiomic profiling of somatic mutations in malformations of cortical development

This study identifies 69 mutated genes in malformations of cortical development using multiomic profiling of 317 brain resections and single-cell sequencing.

Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy and periventricular calcifications

Sperm mosaicism predicts transmission of de novo mutations to human blastocysts

The paper assesses the transmission of de novo mutations from sperm to blastocysts in couples undergoing IVF and finds predictable but slightly under-transmitted mutations based on sperm mutational abundance.

A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

This study shows that autism spectrum disorder risk is influenced by rare variants, polygenic risk, and sex, with sex-specific effects on genetic liability and behavioral traits.

Somatic mosaicism in the mature brain reveals clonal cellular distributions during cortical development

The paper evaluates brain somatic mosaicism in the adult human to identify rules governing cellular distribution during embryogenesis.

Evaluating Human Mutation Databases for 'Treatability' Using Personalized Antisense Oligonucleotides

The paper evaluates human mutation databases to identify treatable variants using antisense oligonucleotides, finding most pathogenic variants could be targeted therapeutically.

Temporal stability of human sperm mosaic mutations results in life-long threat of transmission to offspring

The paper analyzes sperm mosaic mutations in healthy males, finding that many are stable over time and pose a lifelong transmission risk to offspring.

Loss of C2orf69 defines a fatal auto-inflammatory mitochondriopathy in Humans and Zebrafish

The paper identifies C2orf69 deficiency as a cause of a fatal auto-inflammatory syndrome in humans and zebrafish, affecting mitochondrial function and immune/cNS development.

Comprehensive identification of somatic nucleotide variants in human brain tissue

This study identifies somatic SNVs in non-cancerous human brain tissues and establishes best practices for detecting low-frequency variants.