James R. Lupski

Unveiling the Hidden Rules: Enhancing NMD Prediction for Protein-Truncating Variants

The paper develops a model to predict NMD outcomes for protein-truncating variants using RNA-seq data, achieving ~78% ROC-AUC and identifying non-canonical determinants.

DE NOVO VARIANTS IN THE POLY(RC)-BINDING PROTEIN GENE PCBP1 CAUSE A NEURODEVELOPMENTAL DISORDER

The paper identifies de novo variants in PCBP1 causing neurodevelopmental disorders, showing impaired dendritic arborization and increased exon skipping in T cells.

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.

Building an Interoperable Rare Disease Multi-omic Resource: The GREGoR Data Model and Dataset

The paper introduces a data model and dataset for rare disease research, enabling interoperable multi-omic data integration across clinical sites.

Autosomal dominant CDC45 deficiency with allelic expression bias causes a novel genetic disease of the immune system

The paper identifies a CDC45 variant causing immune disease with allelic bias, linking it to NK cell dysfunction and variable expressivity in a family.

Familial medullary thyroid carcinoma secondary to an SLC30A9 intragenic deletion and translation reinitiation

The paper identifies an SLC30A9 deletion causing familial medullary thyroid carcinoma through translation reinitiation and shows its oncogenic effects.

CHANGER: A novel genetic reference from 902 unrelated Chilean exomes to enhance South American medical genetics and research.

The paper presents CHANGER, a Chilean exome reference dataset of 902 unrelated individuals, to improve genetic research and variant interpretation in South American populations.

Phase Separation Contributes to Pathogenicity for Nonsense Mediated Decay-Escaping Variant Alleles

This study identifies NMD-escape variants as a distinct class of disease-causing mutations, showing that altered C-terminal regions drive pathogenicity through phase separation.

Allele-specific correction of ATAD3A pathogenic variants via template-free CRISPR-Cas9 editing and gene conversion

This study corrects a pathogenic ATAD3A variant in iPSCs using CRISPR-Cas9-induced gene conversion without donor templates, showing high efficiency and dependence on HR proteins.

Improving Automated Deep Phenotyping Through Large Language Models Using Retrieval Augmented Generation

RAG-HPO improves HPO term assignment using retrieval-augmented generation, achieving higher precision and recall than existing tools in phenotypic analysis of clinical text.

Biallelic variants in the non-coding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes

The paper identifies biallelic variants in RNU4-2 causing a recessive neurodevelopmental syndrome with distinct white matter changes, expanding the known genotypic and phenotypic spectrum of RNU4-2-related disorders.

Pathogenic DVL frameshifting variants in Robinow syndrome disrupt WNT signaling and cellular dynamics

The paper investigates how pathogenic DVL frameshifting variants in Robinow syndrome disrupt WNT signaling and cellular dynamics by altering protein structure and function.

EPHA4 signaling dysregulation links abnormal locomotion and the development of idiopathic scoliosis

This study identifies EPHA4 signaling dysregulation as a contributor to idiopathic scoliosis by linking it to locomotion defects and CPG network disruption in zebrafish.

Genomic rare variant mechanisms for congenital cardiac laterality defect: A digenic model approach

The paper identifies trans-heterozygous digenic variants in laterality defect genes using exome/genome sequencing data from CHD cohorts, finding significant enrichment in laterality cases compared to controls.

RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS

The paper identifies SPOUT1/CENP-32 as a causative gene for SpADMiSS, linking its dysfunction to mitotic spindle defects and neurodevelopmental disorders.

Defining and Reducing Variant Classification Disparities

The paper analyzes variant classification disparities between European-like and non-European-like genetic ancestries and shows that MAVE data can reduce these disparities in VUS reclassification.

VizCNV: An integrated platform for concurrent phased BAF and CNV analysis with trio genome sequencing data

VizCNV is a tool for analyzing CNVs and phased BAF from trio genome sequencing data, identifying de novo and inherited CNVs in immunodeficiency cases.

A novel neurodevelopmental syndrome caused by loss-of-function of the Zinc Finger Homeobox 3 (ZFHX3) gene

This paper identifies loss-of-function variants in ZFHX3 as a cause of syndromic intellectual disability and describes its role in chromatin remodeling and DNA methylation.

Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders

The paper identifies biallelic FLVCR1 variants causing a range of neurodevelopmental and neurodegenerative disorders, linking them to choline and ethanolamine transport dysfunction.

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.

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.

Break-induced replication underlies formation of inverted triplications and generates unexpected diversity in haplotype structures

The paper investigates DUP-TRP/INV-DUP genomic rearrangements in neurodevelopmental disorders, identifying four SV haplotypes and refining template switching points using multiple sequencing technologies.

Missense variants affecting the actin-binding domains of PLS3 cause X-linked congenital diaphragmatic hernia and body wall defects

The paper identifies missense variants in PLS3 causing X-linked congenital diaphragmatic hernia and body wall defects through genetic analysis and functional studies.

Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease

The paper identifies monoallelic DHX9 variants as a cause of neurodevelopmental disorders and Charcot-Marie-Tooth disease, showing genotype-phenotype correlations and cellular dysfunction.

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

The paper demonstrates that recurrent genomic deletions mediated by nonallelic homologous recombination drive recessive disease burden and identifies new disease-contributing variants through exome reanalysis.

Centers for Mendelian Genomics: A decade of facilitating gene discovery

The paper describes the role of the Centers for Mendelian Genomics in advancing gene discovery through data sharing, collaboration, and resource development over the past decade.

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

The paper characterizes the clinical and molecular features of 36 individuals with SETD1B variants, identifying a core phenotype of developmental delay and variable epilepsy, with male predominance and potential sex-linked effects.

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.

Clinical, neuroimaging and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability

The paper describes the clinical, neuroimaging, and molecular features of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability, providing variant interpretation guidelines and carrier frequency estimates.

Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes

The paper identifies and functionally characterizes new ATAD3A variants in neurological disorders using exome sequencing and Drosophila models.