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Heterozygous Variants in PLCG1 Affect Hearing, Vision, Cardiac, and Immune Function
No full textPhospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), important signaling molecules involved in many cellular processes including Ca2+ release from the endoplasmic reticulum (ER). PLCG1 encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations of PLCG1 are observed in multiple cancers, but only one germline variant has been reported. Here, we describe seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] who present with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). To model these variants in vivo, we generated the analogous variants in the Drosophila ortholog, small wing (sl). We created a null allele slT2A and assessed its expression pattern. sl is broadly expressed, including wing discs, eye discs, and a subset of neurons and glia. slT2A mutant flies exhibit wing size reductions, ectopic wing veins, and supernumerary photoreceptors. We document that mutant flies also exhibit a reduced lifespan and age-dependent locomotor defects. Expressing wild-type sl in slT2A mutant flies rescues the loss-of-function phenotypes, whereas the variants increase lethality. Ectopic expression of an established hyperactive PLCG1 variant, p.(Asp1165His) in the wing pouch causes elevated Ca2+ activity and severe wing phenotypes. These phenotypes are also observed when the p.(Asp1019Gly) or p.(Asp1165Gly) variants are overexpressed in the wing pouch, arguing that these are gain-of-function variants. However, the wing phenotypes associated with p.(His380Arg) or p.(Leu597Phe) overexpression are either mild or only partially penetrant. Our data suggest that the heterozygous missense variants reported here affect protein function differentially and contribute to the clinical features observed in the affected individuals.
Research organism: D. melanogaster, Huma
Genome-Wide Prediction of Dominant and Recessive Neurodevelopmental Disorder-Associated Genes
No full textDespite great progress, thousands of neurodevelopmental disorder (NDD) risk genes remain to be discovered. We present a computational approach that accelerates NDD risk gene identification using machine learning. First, we demonstrate that models trained solely on single-cell RNA sequencing data can robustly predict genes implicated in autism spectrum disorder (ASD), developmental and epileptic encephalopathy (DEE), and developmental delay (DD). Notably, we find differences in gene expression patterns of genes with monoallelic and bi-allelic inheritance patterns in the developing human cortex. We then integrate expression data with 300 orthogonal features, including intolerance metrics, protein-protein interaction data, and others, in a semi-supervised machine learning framework (mantis-ml) to train inheritance-specific models for these disorders. The models have high predictive power (area under the receiver operator curves [AUCs]: 0.84-0.95), and the top-ranked genes were up to 2-fold (monoallelic models) and 6-fold (bi-allelic models) more enriched for high-confidence NDD risk genes compared to genic intolerance metrics alone. Additionally, genes ranking in the top decile were 45 to 180 times more likely to have literature support than those in the bottom decile. Collectively, this work provides robust NDD risk gene predictions that can complement large-scale gene discovery efforts and underscores the importance of considering inheritance in gene risk prediction
Drosophila Models Uncover Substrate Channeling Effects on Phospholipids and Sphingolipids in Peroxisomal Biogenesis Disorders
No full textPeroxisomal Biogenesis Disorders Zellweger Spectrum (PBD-ZSD) disorders are a group of autosomal recessive defects in peroxisome formation that produce a multi-systemic disease presenting at birth or in childhood. Well documented clinical biomarkers such as elevated very long chain fatty acids (VLCFA) are key biochemical diagnostic findings in these conditions. Additional, secondary biochemical alterations such as elevated very long chain lysophosphatidylcholines are allowing newborn screening for peroxisomal disease. In addition, a more widespread impact on metabolism and lipids is increasingly being documented by metabolomic and lipidomic studies. Here we utilize Drosophila models of pex2 and pex16 as well as human plasma from individuals with PEX1 mutations. We identify phospholipid abnormalities in Drosophila larvae and brain characterized by differences in the quantities of phosphatidylcholine (PC) and phosphatidylethanolamines (PE) with long chain lengths and reduced levels of intermediate chain lengths. For diacylglycerol (DAG), the precursor of PE and PC through the Kennedy pathway, the intermediate chain lengths are increased suggesting an imbalance between DAGs and PE and PC that suggests the two acyl chain pools are not in equilibrium. Altered acyl chain lengths are also observed in PE ceramides in the fly models. Interestingly, plasma from human subjects exhibit phospholipid alterations similar to the fly model. Moreover, human plasma shows reduced levels of sphingomyelin with 18 and 22 carbon lengths but normal levels of C24. Our results suggest that peroxisomal biogenesis defects alter shuttling of the acyl chains of multiple phospholipid and ceramide lipid classes. In contrast, DAG species with intermediate fatty acids are actually more abundant in PBD. These data suggest an imbalance between de novo synthesis of PC and PE through the Kennedy pathway and remodeling of existing PC and PE through the Lands cycle. This imbalance is likely due to overabundance of very long acyl chains in PBD and a subsequent imbalance due to substrate channeling effects. Given the fundamental role of phospholipid and sphingolipids in nervous system functions, these observations suggest PBD-ZSD are diseases characterized by widespread cell membrane lipid abnormalities
Synaptic Alterations in Pyramidal Cells Following Genetic Manipulation of Neuronal Excitability in Monkey Prefrontal Cortex
No full textThe primate dorsolateral prefrontal cortex (DLPFC) displays unique in vivo activity patterns, but how in vivo activity regulates DLPFC pyramidal neuron (PN) properties remains unclear. We assessed the effects of in vivo Kir2.1 overexpression, a genetic silencing tool, on synapses in monkey DLPFC PNs. We show for the first time that recombinant ion channel expression successfully modifies the excitability of primate cortex neurons, producing effects on synaptic properties apparently different from those in the rodent cortex
Strengthening the Future: Sparking Growth and Connection Among Early Career Librarians
No full textDescription: This presentation highlights innovative programming created to support early career librarians as they develop and grow in their professional roles. Using a case study of an Early Career Librarian Task Force specifically for medical librarians, led by early career librarians themselves, it will showcase the programs developed, share lessons learned, and offer preliminary insights into the unique needs of early career librarians. Learning Objectives: The audience will gain insight into the needs of the next generation of librarians, learn about ways to support early career librarians at their library, and leave with practical guidance for creating their own social events for early career librarians
FlyPhoneDB2: A Computational Framework for Analyzing Cell-Cell Communication in Drosophila scRNA-Seq Data Integrating AlphaFold-Multimer Predictions
No full textCell-cell communication (CCC) plays a critical role in the physiological regulation of organisms and has been implicated in numerous diseases. Previously, we introduced FlyPhoneDB, a tool designed to explore CCC in Drosophila single-cell RNA-sequencing datasets. The core algorithm of FlyPhoneDB infers tissue-specific signaling events between cell types by calculating cell-cell interaction scores based on curated ligand-receptor (L-R) expression across major signaling pathways. However, the utility of FlyPhoneDB was limited by the relatively small number of available L-R pairs.
Here, we present FlyPhoneDB2, a major upgrade featuring a significantly expanded knowledgebase that includes a greater number of L-R pairs, incorporating annotations from mammalian species and structural predictions from AlphaFold-Multimer. In addition, the algorithm has been optimized for improved performance and more effective noise filtering. New functionalities have also been introduced, such as the addition of downstream reporter genes to evaluate pathway activity, multi-sample CCC comparison, and enhanced visualizations summarizing communication at a network level.
We demonstrate the utility of FlyPhoneDB2 by analyzing whole-body single-nuclei RNA-seq datasets from flies with gut tumors induced by the Yorkie oncogene. We show that FlyPhoneDB2 not only recapitulates established biological insights into the Drosophila Yorkie tumor model, but also identifies novel potential L-R pairs that may play important roles in tumor-induced cachexia. FlyPhoneDB2 is available at https://www.flyrnai.org/tools/fly_phone_v2/
The Causal Pivot: A Structural Approach to Genetic Heterogeneity and Variant Discovery in Complex Diseases
No full textWe present the Causal Pivot (CP) as a structural causal model (SCM) for analyzing genetic heterogeneity in complex diseases. The CP leverages an established causal factor or factors to detect the contribution of additional suspected causes. Specifically, polygenic risk scores (PRSs) serve as known causes, while rare variants (RVs) or RV ensembles are evaluated as candidate causes. The CP incorporates outcome-induced association by conditioning on disease status. We derive a conditional maximum-likelihood procedure for binary and quantitative traits and develop the Causal Pivot likelihood ratio test (CP-LRT) to detect causal signals. Through simulations, we demonstrate the CP-LRT’s robust power and superior error control compared to alternatives. We apply the CP-LRT to UK Biobank (UKB) data, analyzing three exemplar diseases: hypercholesterolemia (HC, low-density lipoprotein cholesterol ≥4.9 mmol/L; nc = 24,656), breast cancer (BC, ICD-10 C50; nc = 12,479), and Parkinson disease (PD, ICD-10 G20; nc = 2,940). For PRS, we utilize UKB-derived values, and for RVs, we analyze ClinVar pathogenic/likely pathogenic variants and loss-of-function mutations in disease-relevant genes: LDLR for HC, BRCA1 for BC, and GBA1 for PD. Significant CP-LRT signals were detected for all three diseases. Cross-disease and synonymous variant analyses serve as controls. We further develop ancestry adjustment using matching and inverse probability weighting as well as regression and doubly robust methods; we extend this to examine oligogenic burden in the lysosomal storage pathway in PD. The CP reveals an approach to address heterogeneity and is an extensible method for inference and discovery in complex disease genetics
Osteogenesis Imperfecta and the Family: A Qualitative Analysis of the Experiences of Family and Caregivers
No full textIntroduction: Osteogenesis imperfecta (OI) describes a group of rare, heritable bone disorders causing bone fragility, tendency to fracture with minimal trauma, and chronic pain due to abnormal collagen synthesis. Limited research exists on the psychosocial impact of OI during childhood on caregivers and families.
Purpose: This study aimed to understand caregiver experiences, existing social support provided for families affected by OI, and the impact of OI on family life.
Method: Thirteen caregivers of individuals with OI participated in semistructured interviews. Researchers coded, abstracted, and analyzed qualitative data to develop themes on the psychosocial impact of OI on the family unit.
Results: Analysis yielded four themes: (a) encountering difficult experiences during diagnosis of OI, (b) caregiver well-being and coping, (c) broad family impact, and (d) the existence and further need for social support.
Discussion: Findings have implications for child and caregiver well-being and health care professionals during diagnosis and emphasize the need for social support for families affected by OI. Future research should engage a more diverse (in terms of ethnoracial demographics and family structures) sample and utilize quantitative analyses to complement the present understanding of the relationship between OI and family well-being. (PsycInfo Database Record (c) 2025 APA, all rights reserved)
Ethical Governance for Genomic Data Science in the Cloud
No full textCloud platforms offer distinct advantages, but questions remain about how to ethically and efficiently manage human genomic data in the cloud. Data governance needs to be adapted to ensure transparency and security for research participants, as well as equitable and sustainable access for researchers
Definitions of Cardiogenic Shock and Indications for Temporary Mechanical Circulatory Support: Joint Consensus Report of the PeriOperative Quality Initiative and the Enhanced Recovery After Surgery Cardiac Society
No full textBackground: The management of patients with cardiogenic shock (CS) is complex and resource intensive, particularly given the recent surge in temporary mechanical circulatory support (tMCS) devices. This document was created to establish an approach to the assessment of CS to provide early and targeted therapies, including tMCS.
Methods: An interdisciplinary, international panel of experts, using a structured appraisal of the literature and a modified Delphi method, derived consensus regarding the assessment of CS based on pathophysiologic severity, etiology, and phenotypic clustering to guide escalation of care as well as identify those patients who might benefit from tMCS.
Results: Key principles included early and continuous assessment for the evolution of shock severity to guide the escalation of care as well as establishment of the cause of CS to facilitate triage and assignment of initial therapies. Phenotypic clustering is complementary and aids in prognosis. tMCS provides the greatest benefit in CS for relief of congestion refractory to medical therapy, ideally when initiated before the development of organ injury. The use of tMCS should be preceded by an interdisciplinary discussion as part of the informed consent process to establish therapeutic goals, including exit strategies.
Conclusions: Based on the available literature and expert consensus, there is an opportunity to further standardize the approach to CS, including characterization based on the severity of the shock state, etiology, and further enhancement by phenotyping. Monitoring, early triage, and timely escalation of care, including the targeted initiation of tMCS, can minimize organ injury and in-hospital mortality