Biology subjects

Jeon, H.

Publications and source records attributed to Jeon, H..

36 records · Page 2Linked to original sources

bioRxiv2024

A diverse landscape of FGFR alterations and co-mutations defines novel therapeutic strategies in pediatric low-grade gliomas

Alterations in Fibroblast growth factor receptor (FGFR)-family proteins frequently occur as oncogenes in many cancers, including a subset of pediatric gliomas. Here, we performed a genomic analysis of 11,635 gliomas across ages and found that 4.5% of all gliomas harbor FGFR alterations including structural variants (SV) and single nucleotide variants (SNV), with an incidence of almost 10% in pediatric gliomas. FGFR family members are differentially enriched by age, tumor grade, and histological subtype, with FGFR1-alterations associated with glioneuronal histologies and pediatric low-grade gliomas. Across development, we find FGFR1 expression in both neuronal and glial precursors, while FGFR3 expression is largely restricted to astrocytic lineages. Leveraging novel isogenic model systems, we confirm FGFR1 alterations to be sufficient to activate MAPK and mTOR signaling, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway inhibitors, including pan-FGFR inhibitors. Models driven by FGFR1 SVs exhibited different patterns of sensitivity compared to those driven by SNVs. Finally, we performed a retrospective analysis of clinical responses in children diagnosed with FGFR-driven gliomas and found that targeted MAPK or FGFR-inhibition with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome.

cancer biology↗

bioRxiv2024

A Bioinert Hydrogel Framework for Precision 3D Cell Cultures: Advancing Automated High-Content and High-Throughput Drug Screening

Enhanced drug testing efficiency has driven the prominence of high-content (HC) and high-throughput (HT) screening (HCHTS) in drug discovery and development. However, traditional HCHTS in well-plates often lack complexity of in vivo conditions. 3D cell cultures, like cellular spheroids/organoids, offer a promising alternative by replicating in vivo conditions and improving the reliability of drug responses. Integrating spheroids/organoids into HCHTS requires strategies to ensure uniform formation, systemic function, and compatibility with analysis techniques. This study introduces an easy-to-fabricate, low-cost, safe, and scalable approach to create a bioinert hydrogel-based inverted colloidal crystal (BhiCC) framework for uniform and high-yield spheroid cultivation. Highly uniform alginate microgels were fabricated and assembled into a colloidal crystal template with controllable contact area, creating engineered void spaces and interconnecting channels within agarose-based BhiCC through the template degradation by alginate lyase and buffer. This results in a multi-layered iCC domain, enabling the generation of in-vitro 3D culture models with over 1,000 spheroids per well in a 96-well plate. The unique hexagonal-close-packed (HCP) geometry of iCC structure enables HCHTS through conventional plate reader analysis and fluorescent microscopy assisted by house-developed automated data processing algorithm. This advancement offers promising applications in tissue engineering, disease modeling, and drug development in biomedical research.

bioengineering↗

bioRxiv2024

eLemur: A cellular-resolution 3D atlas of the mouse lemur brain

The gray mouse lemur (Microcebus murinus), one of the smallest living primates, emerges as a promising model organism for neuroscience research. This is due to its genetic similarity to humans, its evolutionary position between rodents and humans, and its primate-like features encapsulated within a rodent-sized brain. Despite its potential, the absence of a comprehensive reference brain atlas impedes the progress of research endeavors in this species, particularly at the microscopic level. Existing references have largely been confined to the macroscopic scale, lacking detailed anatomical information. Here, we present eLemur, a new resource, comprising a repository of high-resolution brain-wide images immunostained with multiple cell type and structural markers, elucidating the cyto- and chemoarchitecture of the mouse lemur brain. Additionally, it encompasses a segmented two-dimensional (2D) reference and 3D anatomical brain atlas delineated into cortical, subcortical, and other vital regions. Furthermore, eLemur includes a comprehensive 3D cell atlas, providing densities and spatial distributions of non-neuronal and neuronal cells across the mouse lemur brain. Accessible via a web-based viewer (https://eeum-brain.com/#/lemurdatasets), the eLemur resource streamlines data sharing and integration, fostering the exploration of new hypotheses and experimental designs using the mouse lemur as a model organism. Moreover, in conjunction with the growing 3D datasets for rodents, non-human primates, and humans, our eLemur 3D digital framework enhances the potential for comparative analysis and translation research, facilitating the integration of extensive rodent study data into human studies. Significance StatementThe gray mouse lemur (Microcebus murinus) represents a promising model for neuroscience research, offering insights into brain structure and function due to its genetic and evolutionary proximity to humans and rodents. Our development of eLemur, a comprehensive 3D digital brain atlas, fills critical gaps in microscopic data availability, enabling nuanced investigations at cellular resolutions. This resource not only enhances our understanding of the mouse lemur brain but also catalyzes broader neuroscience endeavors. By facilitating data sharing and integration, eLemur empowers researchers to explore novel hypotheses and experimental designs. Moreover, its compatibility with existing neuroanatomy frameworks and the growing repository of 3D datasets positions eLemur as a pivotal tool for advancing basic and translational neuroscience studies.

neuroscience↗

bioRxiv2024

Intraplacental injection of human iPSC-derived PDX1+ pancreatic progenitors prolongs Pdx1-deficient mice survival

Interspecies chimeras comprising human tissues have potential for use in disease modeling and regenerative medicine. Here, we successfully transplanted human induced pluripotent stem cell (iPSC)-derived PDX1+ pancreatic progenitor cells into Pdx1-deficient mouse embryos via intraplacental injection. The engrafted human cells predominantly localized to the duodenum, produced insulin, and extended the lifespan of Pdx1-/- mice by up to 10 days after birth. Transcriptomic analyses confirmed human pancreatic gene expression in human cells engrafted into the mouse duodenum. Our findings demonstrated the feasibility of generating interspecies chimeras with functional human pancreatic cells through in utero transplantation of lineage-committed progenitors. This approach circumvents developmental barriers while minimizing ethical concerns associated with PSCs. However, the incomplete rescue of the Pdx1-/- phenotype highlights the need for further research to enhance human cell engraftment and tissue integration. Overall, this study provides a foundation for developing human-animal chimera models for studying human development and regenerative therapies.

cell biology↗

bioRxiv2024

Stimulative piezoelectric nanofibrous scaffolds for enhanced small extracellular vesicle production in 3D cultures

Small extracellular vesicles (sEVs) have great promise as effective carriers for drug delivery. However, the challenges associated with the efficient production of sEVs hinder their clinical applications. Herein, we report a stimulative 3D culture platform for enhanced sEV production. The proposed platform consists of a piezoelectric nanofibrous scaffold (PES) coupled with acoustic stimulation to enhance sEV production of cells in a 3D biomimetic microenvironment. Combining cell stimulation with a 3D culture platform in this stimulative PES enables a 15.7-fold increase in the production rate per cell with minimal deviations in particle size and protein composition compared with standard 2D cultures. We find that the enhanced sEV production is attributable to the activation and upregulation of crucial sEV production steps through the synergistic effect of stimulation and the 3D microenvironment. Moreover, changes in cell morphology lead to cytoskeleton redistribution through cell-matrix interactions in the 3D cultures. This in turn facilitates intracellular EV trafficking, which impacts the production rate. Overall, our work provides a promising 3D cell culture platform based on piezoelectric biomaterials for enhanced sEV production. This platform is expected to accelerate the potential use of sEVs for drug delivery and broad biomedical applications.

bioengineering↗

bioRxiv2023

Fluorescent Chiral Quantum Dots to Unveil Origin-Dependent Exosome Uptake and Cargo Release

Exosomes are promising nanocarriers for drug delivery. Yet, it is challenging to apply exosomes in clinical use due to the limited understanding of their physiological functions. While cellular uptake of exosomes is generally known through endocytosis and/or membrane fusion, the mechanisms of origin-dependent cellular uptake and subsequent cargo release of exosomes into recipient cells are still unclear. Herein, we investigated the intricate mechanisms of exosome entry into recipient cells and the intracellular cargo release. In this study, we utilized chiral graphene quantum dots (GQDs) as representatives of exosomal cargo, taking advantage of the superior permeability of chiral GQDs into lipid membranes, as well as their excellent optical properties for tracking analysis. We observed a higher uptake rate of exosomes in their parental recipient cells. However, these exosomes were predominantly entrapped in lysosomes through endocytosis (intraspecies endocytic uptake). On the other hand, in non-parental recipient cells, exosomes exhibited a greater inclination for cellular uptake through membrane fusion, followed by direct cargo release into the cytosol (cross-species direct fusion uptake). We revealed the underlying mechanisms involved in the cellular uptake and the subsequent cargo release of exosomes depending on their cell-of-origin and recipient cell types. This study envisions valuable insights into further advancements in the effective drug delivery using exosomes, as well as a comprehensive understanding of cellular communication, including disease pathogenesis.

bioengineering↗

bioRxiv2023

Combinatorial CRISPR screen reveals FYN and KDM4 as targets for synergistic drug combination for treating triple negative breast cancer

Tyrosine kinases play a crucial role in cell proliferation and survival and are extensively investigated as targets for cancer treatment. However, the efficacy of most tyrosine kinase inhibitors (TKIs) in cancer therapy is limited due to resistance. In this study, we identify a synergistic combination therapy involving TKIs for the treatment of triple negative breast cancer. By employing pairwise tyrosine kinase knockout CRISPR screens, we identify FYN and KDM4 as critical targets whose inhibition enhances the effectiveness of TKIs, such as NVP-ADW742 (IGF-1R inhibitor), gefitinib (EGFR inhibitor), and imatinib (ABL inhibitor) both in vitro and in vivo. Mechanistically, treatment with TKIs upregulates the transcription of KDM4, which in turn demethylates H3K9me3 at FYN enhancer for FYN transcription. This compensatory activation of FYN and KDM4 contributes to the resistance against TKIs. FYN expression is associated with therapy resistance and persistence by demonstrating its upregulation in various experimental models of drug-tolerant persisters and residual disease following targeted therapy, chemotherapy, and radiotherapy. Collectively, our study provides novel targets and mechanistic insights that can guide the development of effective combinatorial targeted therapies, thus maximizing the therapeutic benefits of TKIs.

cancer biology↗

bioRxiv2023

Metastatic prognostic ability of lung cancer stromal cells from a single-cell RNA-seq perspective

Single-cell RNA sequencing (scRNA-seq) has been widely studied and analyzed to understand cancer heterogeneity. Metastasis and invasion through communication with immune cells have been widely studied; stromal cells are known to change during cancer progression and cause metastasis, but little is known about their inherent metastasis prognostic abilities. This study investigated the abilities of stromal cells by analyzing the scRNA-seq data of adjacent, tumor, and metastasized tissues, biopsied from 15 patients. We considered fibroblast and smooth muscle cells as cell subtypes of stromal cells. We detected decorin (DCN) and insulin-like growth factor-binding protein 7 (IGFBP7) as sub-cell type markers conserved in tumor and metastasis. We found an organic relationship that affects metastasis by assessing the interaction between the expression and related pathways among the assigned stromal cell subtypes. In addition to the interactions of sub-cell-types within stromal cells, we also studied communication between stromal cells and the five assigned lung cancer cell types, and observed its relation with migration and metastasis; the role of DCN as a mediating factor was also studied. Results of our study indicated that DCN and IGFBP7 are factors that can be monitored in the follow-up of prognostic metastasis factors in patients with lung cancer. Therefore, DCN and IGFBP7, which are the assigned sub-cell types marker in lung cancer stromal cells, can be used as potential biomarkers for follow-up in lung cancer metastasis. Our study assigned stromal cell subtypes of lung cancer and detected markers that can be used as monitoring factors during metastasis of lung cancer. This suggests that DCN and IGFBP7 are potential biomarkers to evaluate metastatic ability and follow-up as metastatic prognostic factors in lung cancer patients. Author SummaryLung cancer is known to be a disease with high heterogeneity. In particular, it has been studied that stromal cells of lung cancer are involved in metastasis in cancer. Finding specific markers of stromal cell subtypes can lead to more accurate cancer markers. In this study, we assigned stromal cell subtypes as FB and SMC through scRNA-seq data analysis. DCN and IGFBP7, which are markers specifically expressed in stromal cell sub-cell types of NSCLC and metastatic NSCLC, were found. Whether DCN and IGFBP7 can be used as prognostic factors for metastasis was verified through co-expression analysis of FB and SMC and cell-cell communication. Specific expression as a marker was verified by confirming the role in the hub-gene network and the target genes of communication. Our findings suggest that DCN and IGFBP7 are potential biomarkers for evaluating the metastasis prognostic ability of stromal cells and can be monitored in the follow-up of metastasis prognostic factors in lung cancer patients.

bioinformatics↗

bioRxiv2023

Chirality-Enhanced Transport and Drug Delivery of Graphene Nanocarriers to Tumor-like Cellular Spheroid

Chirality, defined as "a mirror image," is a universal geometry of biological and nonbiological forms of matter. This geometry of molecules determines how they interact during their assembly and transport. With the development of nanotechnology, many nanoparticles with chiral geometry or chiroptical activity have emerged for biomedical research. The mechanisms by which chirality originates and the corresponding synthesis methods have been discussed and developed in the past decade. Inspired by the chiral selectivity in life, a comprehensive and in-depth study of interactions between chiral nanomaterials and biological systems has far-reaching significance in biomedicine. Here, we investigated the effect of the chirality of nanoscale drug carriers, graphene quantum dots (GQDs), on their transport in tumor-like cellular spheroids. Chirality of GQDs (L/D-GQDs) was achieved by the surface modification of GQDs with L/D-cysteines. As an in-vitro tissue model for drug testing, cellular spheroids were derived from a human hepatoma cell line (i.e., HepG2 cells) using the Hanging-drop method. Our results reveal that the L-GQDs had a 1.7-fold higher apparent diffusion coefficient than the D-GQDs, indicating that the left-handed chirality of GQDs can enhance their transport into tumor-like cellular spheroids. Moreover, when loaded with a common chemotherapy drug, Doxorubicin (DOX), via {pi}-{pi} stacking, L-GQDs are more effective as nanocarriers for drug delivery, resulting in 25% higher efficacy for cancerous cellular spheroids than free DOX. Overall, our studies indicated that the chirality of nanocarriers is essential for the design of drug delivery vehicles to enhance the transport of drugs in a cancerous tumor.

bioengineering↗

bioRxiv2023

Distinct prefrontal projections conversely orchestrate social competition and hierarchy

Social animals compete for limited resources, resulting in a social hierarchy. Although different neuronal subpopulations in the medial prefrontal cortex (mPFC), a hub brain region of social hierarchy, encode distinct social competition behaviors, their identities and associated molecular underpinnings have not yet been identified. In this study, we found that mPFC neurons projecting to the nucleus accumbens (mPFC-NAc) encode social winning behavior, whereas mPFC neurons projecting to the ventral tegmental area (mPFC-VTA) encode social losing behavior by monitoring and manipulating neural circuit activity. High-throughput single-cell transcriptomic analysis and projection-specific genetic manipulation revealed that the expression level of POU domain, class 3, transcription factor 1 (Pou3f1) in mPFC-VTA neurons controls social hierarchy. Optogenetic activation of mPFC-VTA neurons increases Pou3f1 expression and lowers social rank. Together, these data demonstrate that discrete activity and gene expression in separate mPFC projections oppositely orchestrate social competition and hierarchy.

neuroscience↗

bioRxiv2022

Label-free and high-throughput removal of residual undifferentiated cells from iPSC-derived spinal-cord progenitor cells

The transplantation of spinal cord progenitor cells (SCPCs) derived from human induced pluripotent stem cells (iPSCs) has beneficial effects on treating spinal cord injury (SCI). However, the presence of residual undifferentiated iPSCs amongst their differentiated progeny poses a high risk as it can develop teratomas or other types of tumors post-transplantation. Despite the need to remove these residual undifferentiated iPSCs, no specific surface markers can identify them for subsequent removal. By profiling the size of SCPCs after a 10-day differentiation process, we found that the large-sized group contains significantly more cells expressing pluripotent markers. In this study, we employed a sized-based, label-free separation using an inertial microfluidic-based device to remove tumor-risk cells. The device can reduce the number of undifferentiated cells from an SCPC population with high throughput (i.e., > 3 million cells per minute) without affecting cell viability and functions. The sorted cells were verified with immunofluorescence staining, flow cytometry analysis, and colony culture assay. We demonstrated the capabilities of our technology to reduce the percentage of OCT4-positive cells. Our technology has great potential for the downstream processing of cell manufacturing workflow, ensuring better quality and safety of transplanted cells.

bioengineering↗

bioRxiv2022

Cryo-EM structure of a RAS/RAF recruitment complex

Cryo-EM structures of a KRAS/BRAF/MEK1/14-3-3 complex reveal KRAS bound to the flexible Ras-binding domain of BRAF, captured in two orientations. Autoinhibitory interactions are unperturbed by binding of KRAS and in vitro activation studies confirm that KRAS binding is insufficient to activate BRAF, absent membrane recruitment. These structures illustrate the separability of binding and activation of BRAF by Ras and suggest stabilization of this pre-activation intermediate as an alternative to blocking binding of KRAS.

biochemistry↗

bioRxiv2022

The Phytophthora capsici RxLR effector CRISIS2 has roles in suppression of PTI and triggering cell death in host plant

Pathogen effectors can suppress various plant immune responses, suggesting that they have multiple targets in the host. To understand the mechanisms underlying plasma membrane-associated and effector-mediated immunity, we performed Phytophthora capsici RxLR cell death Inducer Suppressing Immune System (CRISIS) screening. In Nicotiana benthamiana, the cell death induced by the RxLR effector CRISIS2 is inhibited by the irreversible plasma membrane H+-ATPase (PMA) activator fusicoccin. Biochemical and gene silencing analyses revealed that CRISIS2 physically and functionally associates with PMAs and induces host cell death independent of immune receptors. CRISIS2 induces apoplastic alkalization by suppressing PMA activity via its association with the C-terminal regulatory domain of PMA. In planta expression of CRISIS2 significantly enhanced the virulence of P. capsici, whereas host-induced gene silencing of CRISIS2 compromised disease symptom and biomass of P. capsici. Furthermore, co-immunoprecipitation assays revealed that CRISIS2 constitutively associates with BAK1, the co-receptor of pattern recognition receptors (PRRs). CRISIS2 interferes with the FLS2-BAK1 complex induced by flagellin perception and impairs downstream signaling from the PRR complex. Proteomics and gene silencing assays identified putative PRRs that negatively regulate the virulence of P. capsici in N. benthamiana as interactors of CRISIS2 and BAK1. Our study identified a novel RxLR effector playing multiple roles in the suppression of plant defense and induction of cell death to support the pathogen hemibiotrophic life cycle in the host plant.

plant biology↗

bioRxiv2022

Mosaic receptor-binding domain nanoparticles induce protective immunity against SARS-CoV-2 challenges

Recurrent spillovers of - and {beta}-coronaviruses (CoV) such as acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, SARS-CoV-2, and possibly human CoV (NL63, 229E, OC43, and HKU1) have caused serious morbidity and mortality worldwide. Six receptor binding domains (RBDs) derived from - and {beta}-CoV that are considered to have originated from animals and cross-infected humans were linked to proliferating cell nuclear antigen (PCNA) heterotrimeric subunits, PCNA1, PCNA2, and PCNA3. These were used to form a scaffold-based mosaic multivalent antigen, 6RBD-np. Electron microscopic and atomic force microscopic images show a ring-shaped disk with six protruding RBDs, like jewels in a crown, with a size of 40 nm. Prime-boost immunizations with 6RBD-np in BALB/c mice elicited strong, dose-dependent antibody responses. In human angiotensin converting enzyme 2-transgenic mice, the same immunization induced full-protection against SARS-CoV-2 wild type and Delta challenges, resulting in a 100% survival rate. The mosaic 6RBD-np provides a potential platform for developing a pan-CoV vaccine against newly emerging SARS-CoV-2 variants and future CoV spillovers. SignificanceDespite the arsenal of COVID-19 vaccines, hospitalization and mortality associated with SARS-CoV-2 (acute respiratory syndrome coronavirus 2) variants remain high. There is an urgent need to develop next-generation COVID vaccines that provide broad protection against diseases by current and newly emerging SARS-CoV-2 variants. In this study, six receptor binding domains (RBDs) derived from - and {beta}-CoV were linked to proliferating cell nuclear antigen (PCNA) heterotrimeric scaffolds. They assemble to create a stable mosaic multivalent nanoparticle, 6RBD-np, displaying a ring-shaped disk with six protruding antigens. The prime-boost immunization in BALB/c and human angiotensin converting enzyme 2-transgenic mice with the 6RBD-np elicited strong, dose-dependent antibody responses and induced full-protection against both the SARS-CoV-2 wild type (WT) and Delta challenges. This study provides proof-of-concept that the mosaic 6RBD-np induces 100% protection against SARS-CoV-2 WT and Delta. It provides the potential of co-displaying heterologous antigens for novel vaccine designs, which can be deployed countering future pandemics.

bioengineering↗

bioRxiv2021

Topographic connectivity and cellular profiling reveal detailed input pathways and functionally distinct cell types in the subthalamic nucleus

The subthalamic nucleus (STN) controls psychomotor activity and is an efficient therapeutic deep brain stimulation target in Parkinsons disease patients. Despite evidence indicating position-dependent therapeutic effects and distinct functions within the STN, input circuit and cellular profile in the STN remain largely unclear. Using advanced neuroanatomical techniques, we constructed a comprehensive connectivity map of the indirect and hyperdirect pathways in both the mouse and human STN. Our detailed circuit- and cellular-level connectivity revealed a topographically graded organization with three convergent types of indirect and hyperdirect-pathways. Furthermore, we identified two functional types of glutamatergic STN neurons (parvalbumin, PV +/- neurons) segregated with a topographical distribution. Glutamatergic PV+ STN neurons contribute to burst firing. We confirmed synaptic connectivity from indirect and hyperdirect pathways to both PV+ and PV-. These data suggest a complex interplay of information integration within the basal ganglia underlying coordinated movement control and therapeutic effects.

neuroscience↗

bioRxiv2021

Crowdsourced Identification of Multi-Target Kinase Inhibitors for RET- and TAU- Based Disease: the Multi-Targeting Drug DREAM Challenge

A continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple reasons including lack of efficacy, rapidly acquired drug resistance, and narrow patient eligibility criteria. An alternative approach is the development of drugs that address the overall disease network by targeting multiple biological targets ( polypharmacology). Rational development of these molecules will require improved methods for predicting single chemical structures that target multiple drug targets. To address this need, we developed the Multi-Targeting Drug DREAM Challenge, in which we challenged participants to predict single chemical entities that target pro-targets but avoid anti-targets for two unrelated diseases: RET-based tumors and a common form of inherited Tauopathy. Here, we report the results of this DREAM Challenge and the development of two neural network-based machine learning approaches that were applied to the challenge of rational polypharmacology. Together, these platforms provide a potentially useful first step towards developing lead therapeutic compounds that address disease complexity through rational polypharmacology. Author SummaryMany modern drugs are developed with the goal of modulating a single cellular pathway or target. However, many drugs are, in fact, dirty; they target multiple cellular pathways or targets. This phenomenon is known as multi-targeting or polypharmacology. While some strive to develop cleaner therapeutics that eliminate secondary targets, recent work has shown that multi-targeting therapeutics have key advantages for a variety of diseases. However, while multi-targeting drugs that affect a precisely-defined profile of targets may be more effective, it is difficult to computationally predict which molecules have desirable target profiles. Here, we report the results of a competitive crowdsourcing project (the Multi-Targeting Drug DREAM Challenge), where we challenged participants to predict chemicals that have desired target profiles for cancer and neurodegenerative disease.

pharmacology and toxicology↗

bioRxiv2019

Resolvin D3 controls mouse and human nociceptive functions and preclinical progression of psoriasis

Psoriasis is a chronic inflammatory skin disease caused by a complex interplay between the immune and nervous systems. Here, we found that resolvin D3 (RvD3) significantly prevented both skin inflammation and itch in a preclinical animal model of psoriasis induced by repeated applications of imiquimod. We also found that RvD3 anti-psoriatic effects resulted from the inhibition of nociceptive functions, which inhibition was replicated in human nociceptive neurons. We conclude that RvD3 and targeting nociceptive functions are promising strategies to treat psoriasis.

neuroscience↗

bioRxiv2019

Genomic profiling of 553 uncharacterized neurodevelopment patients reveals a high proportion of recessive pathogenic variant carriers in an outbred population

BackgroundA substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking.\n\nMethodsGenetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Pathogenic variants were selected and evaluated based on a comparison to patient symptoms and genetic properties of the variants were analyzed.\n\nResultsDisease-causing variants, including newly discovered variants, were identified in in 57.5% of the probands of the KND cohort. Of the 553 patients, 47.4% harbored variants that were previously reported as being pathogenic, and 35.1% of the previous reported pathogenic variants were inherited in a recessive manner. Genes that cause recessive disorders tend to be less constrained by loss-of-function variants and enriched in metabolic and mitochondrial pathways. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated.\n\nConclusionsWe suggest that the odds are high for healthy individuals carrying a potentially pathogenic variant, and its genetic properties. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.

genetics↗