Biology subjects

Zweier, C.

Publications and source records attributed to Zweier, C..

5 recordsLinked to original sources

bioRxiv2026

SysNDD: A Systematic Database for Neurodevelopmental Disorders

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogeneous, and evidence linking additional genes to disease evolves rapidly. We developed SysNDD, an open-access, expert-curated resource that represents distinct gene-inheritance-disease associations as entities with standardized confidence, phenotype, and variant annotations. Each entity retains its curation history, so its evidence category can change as evidence accumulates. Currently, SysNDD contains 4,275 entities curated from 4,932 publications. Of these, 3,758 entities involving 3,271 genes describe NDDs; the remainder record non-NDD disorders, nearly all linked to NDD-associated genes, included for completeness. Regarding NDD evidence categories, 1,838 genes are Definitive, 179 Moderate, 1,248 Limited, and 6 Refuted. The entity model captures inheritance-specific disorders, including 220 genes with both autosomal dominant and autosomal recessive NDD associations. Comparison with seven other NDD gene resources showed complementary coverage, and evidence categories largely agreed with those of ClinGen, Gene2Phenotype, and PanelApp for shared gene-disease pairs. NDD genes formed distinct molecular modules, whereas associated disorders formed broad, overlapping phenotype groups that corresponded to those modules only selectively. SysNDD provides a continuously maintained, programmatically accessible framework for gene-disease evidence assessment, inheritance-aware interpretation, and systematic NDD research.

genetics↗

bioRxiv2021

NRF1 Association with AUTS2-Polycomb Mediates Specific Gene Activation in the Brain

The heterogeneous complexes comprising the family of Polycomb Repressive Complex 1 (PRC1) are instrumental to establishing facultative heterochromatin that is repressive to transcription. Yet, two PRC1 species, PRC1.3 and PRC1.5, are known to comprise novel components, AUTS2, P300, and CK2 that convert this repressive function to that of transcription activation. Here, we report that patients harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mostly associated with a heterozygous pathogenic variant in CREBBP/EP300. As well, the absence of AUTS2 gives rise to a mis-regulation of a subset of developmental genes and curtails motor neuron differentiation from embryonic stem cells in the context of a well-defined system. Moreover, the transcription factor, Nuclear Respiratory Factor 1 (NRF1) exhibits a novel and integral role in this aspect of the neurodevelopmental process, being required for PRC1.3 recruitment to chromatin.

biochemistry↗

bioRxiv2020

De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

High-impact pathogenic variants in more than 1,000 protein-coding genes cause Mendelian forms of neurodevelopmental disorders (NDD), including the newly reported AGO2 gene. This study describes the molecular and clinical characterization of 28 probands with NDD harboring heterozygous AGO1 coding variants. De novo status was always confirmed when parents were available (26/28). A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Some variants were recurrently identified in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linkers domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behavior and additional behavioral manifestations. Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to AGO2 phenotype.

genetics↗

bioRxiv2019

Prenatal diagnosis of HNF1B-associated renal cysts: Need to differentiate intragenic variants from 17q12 microdeletion syndrome?

ObjectiveLarge deletions of chromosome 17q12 (17q12DS) or intragenic variants in HNF1B are associated with variable developmental, endocrine and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe pre- and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to previous studies.\n\nMethodsPrenatal sequencing and postnatal chromosomal microarray analysis was performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants.\n\nResultsIn a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA binding domain, a mutational hotspot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions of varying size. Literature screening revealed highly variable reporting of HNF1B-associated clinical traits. Overall, developmental delay was more frequent in 17q12DS carriers, although both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum.\n\nConclusionsWe highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants is necessary for a more accurate risk quantification of pre- and postnatal clinical features, improving genetic counseling and prenatal decision-making.

genetics↗

bioRxiv2018

Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

BackgroundAlthough habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood.\n\nMethodsWe manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with habituation deficits.\n\nResultsWe identified more than 100 genes required for habituation learning. For the vast majority of these, 93 genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with overgrowth/macrocephaly and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response.\n\nConclusionsOur work demonstrates the relevance of habituation learning to autism, identifies an unprecedented number of novel habituation players, supports an emerging role for inhibitory neurons in habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes habituation as a possible, widely applicable target for pharmacologic intervention in ID/ASD.

neuroscience↗