Biology subjects

Park, J.-Y.

Publications and source records attributed to Park, J.-Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Molecular-level analysis of serum IgG repertoires in COVID-19-vaccinated people with cystic fibrosis identifies abundant convergent antibodies

BackgroundPeople with cystic fibrosis (pwCF) are at increased risk of severe disease following respiratory viral infections including influenza and respiratory syncytial virus, and were therefore given priority for COVID-19 vaccination. Retrospective epidemiological data have revealed a lower incidence of SARS-CoV-2 infection and a reduced fatality rate among pwCF than in the general population, possibly from the stringent infection control measures and early adoption of protective behaviors. Despite several reports of adequate binding and neutralizing titers after vaccination, the molecular features of vaccine-elicited serum antibody repertoires in pwCF remain unknown. MethodsWe performed high-resolution proteomic analysis of serum IgG, combined with next-generation sequencing of B cells, to quantitatively profile Spike (S)-reactive serological repertoires from nine infection-naive pwCF after two doses of COVID-19 mRNA vaccine. We recombinantly expressed 20 IgG clonotypes from 6 pwCF as monoclonal antibodies (mAbs) and measured their binding and neutralization against vaccine-strain and variant viruses. ResultsAll donors mounted strong binding and neutralizing titers to vaccine-strain virus. Ig-Seq revealed diverse serum repertoires in all vaccinees, with antibodies targeting the receptor-binding domain (RBD) comprising 64% of each circulating repertoire by abundance. Several serum IgG clonotypes identified across our cohort shared identical or similar IGHV and CDRH3 amino acid sequences with serum IgG from other pwCF or S-reactive mAbs isolated from non-CF individuals. These convergent antibodies made up 14.6% of the anti-S repertoires in our cohort, reaching 24.8% in one pwCF. Convergent antibodies tended to be RBD-reactive and enriched in specific IGHV; surprisingly, a higher abundance of convergent antibodies in serum correlated with a lower breadth of serum neutralization. All 20 mAbs bound Wuhan S with high affinity (EC50 < 10 nM), and only RBD-reactive mAbs conferred neutralization to vaccine or variant pseudovirus. While most mAbs bound both the B.1.617.2 (Delta, 17/20) and B.1.1.529 (Omicron, 12/20) strains, convergent mAbs were less likely to bind either variant. ConclusionsPost-vaccine serum IgG repertoires in pwCF are dominated by RBD-focused, high-affinity antibodies and include a substantial convergent component shared with non-CF vaccinees. These findings demonstrate that pwCF mount antibody responses comparable to the general population, and a large group of convergent antibodies may contribute to strain-specific rather than cross-variant immunity.

immunology↗

bioRxiv2026

NGFR/Ngfr-marked basal duct progenitors drive ductal--acinar regeneration in injured salivary glands

Severe salivary gland injury can cause chronic xerostomia and persistent secretory dysfunction, yet the epithelial populations that support repair remain poorly defined. Here, we identify NGFR/Ngfr as a conserved surface marker for isolating organoid-forming epithelial stem/progenitor cells from human and mouse salivary glands and show that mouse Ngfr-lineage cells contribute to ductal-acinar regeneration after injury. Single-cell transcriptomic analysis of human salivary gland tissue identified a restricted NGFR-expressing basal duct epithelial subpopulation with progenitor-like features and early positions along inferred epithelial differentiation trajectories. Functionally, NGFR-expressing cells showed enhanced primary and secondary organoid-forming capacity, and NGFR-enriched human organoids engrafted after transplantation into injured salivary glands of immunodeficient mice. In mouse salivary glands, isolated Ngfr-expressing cells showed enriched organoid-forming activity, and Ngfr expression localized to injury-associated ductal regions after duct ligation and local inflammatory injury. Ngfr-CreERT2 lineage tracing further showed that Ngfr-lineage cells contribute to ductal and acinar compartments during post-injury regeneration. Together, these findings establish NGFR/Ngfr as a conserved surface marker for prospectively isolating basal duct epithelial stem/progenitor populations with organoid-forming activity and injury-responsive ductal-acinar regenerative potential.

cell biology↗

bioRxiv2026

A self-limiting orexin-habenula circuit for stress resilience

Resilience requires neural systems that mobilise active coping during stress while limiting its persistence to preserve homeostasis under sustained challenge1-4. Here we identify a self-limiting orexin-habenula circuit in which lateral hypothalamic orexin neurons engage aromatic L-amino acid decarboxylase-expressing D-neurons (encoded by Ddc) in the lateral habenula via orexin receptor type 2 (OX2R)5-7. Activation of this pathway increased nucleus accumbens dopamine and promoted active coping and positive valence. Optotagging revealed rapid stress-evoked recruitment followed by post-stress suppression. In lateral habenula neurons, orexin peptides exerted dissociable effects: orexin-A engaged an OX2R-dependent inhibitory programme superimposed on a parallel inward current, whereas orexin-B did not reproduce this inhibitory profile and instead exerted a distinct membrane effect. Chronic stress disrupted this buffering system through coordinated inflammatory activation, promoter methylation and erosion of D-neuron identity and orexin responsiveness. Restoring orexin-A reversed behavioural and molecular deficits through OX2R-dependent suppression of nuclear factor kappa B signalling, preservation of Tet2 expression, and demethylation-linked maintenance of the Ddc programme. Together, these findings define a self-limiting orexin-habenula resilience circuit that enables adaptive coping while constraining stress-induced vulnerability.

neuroscience↗

bioRxiv2025

FAM84B facilitates tau propagation via RYR3-mediated exocytosis in response to neuroinflammation

The increasing prevalence of dementia underscores the pressing need for effective therapeutic interventions. Despite extensive research into A{beta}, the limited efficacy of existing treatment modalities necessitates a paradigm shift toward tau pathology including tau propagation to slow dementia progression. Here, we identified a novel protein, FAM84B (also known as LRATD2), involved in tau propagation. Elevated FAM84B levels were detected in the postmortem cortex, cerebrospinal fluid, and induced pluripotent stem cell-derived cortical neurons of patients with tauopathy. FAM84B facilitates tau secretion through exosome assembly and RYR3-mediated exocytosis, followed by exosomal uptake into neighboring cells via clathrin-mediated endocytosis, thereby driving tau propagation. We confirmed that neuroinflammation induced by heightened STAT3 activity and cytokine treatment upregulated FAM84B expression, stimulating tau propagation, as evidenced by reduced propagation upon RYR3 inhibition. These findings provide invaluable insights into potential avenues for targeting tau propagation to ameliorate disease progression in tauopathies.

neuroscience↗

bioRxiv2025

Update on the reproduction and interpretation of DIANA fMRI

Three years ago, our group reported direct imaging of neuronal activity (DIANA) with high spatiotemporal resolution, but its reproducibility and signal origin remain controversial. Here, we report the results of our reproduction experiments of DIANA fMRI performed to date using forelimb electrical stimulation at various magnetic field strengths in anesthetized mice, along with the characteristics of DIANA signal, called the pseudo-steady state (PSS). Theoretical analysis and Bloch simulations demonstrated that the spatial location and temporal phase of PSS oscillations are primarily determined by frequency-offset, and that their spatiotemporal superposition can generate peak signals in specific regions at specific timing that closely resemble DIANA signals. These findings suggest that if PSS oscillations are the primary source of DIANA signals, it may be premature to interpret them as neuronal responses to sensory stimulation. Further studies are needed to clarify the relationship between DIANA signals and brain activation.

neuroscience↗

bioRxiv2025

Phosphorylation of a bacterial response regulator by noncognate kinase links carbon catabolite repression to phosphate starvation response

The PhoP-PhoR two-component system regulates transcription of the Pho regulon to counteract inorganic phosphate (Pi) limitation. Interestingly, in a ccpA mutant lacking the global regulator of carbon catabolism, Pho regulon genes are hyper-induced in a PhoR-independent, glucose-dependent manner. While CcpA is known to directly repress the phoP promoter, we now show that overexpression of a phosphorylatable form of PhoP is essential for this hyper-induction. Remarkably, we detected early PhoP phosphorylation in the ccpA phoR double mutant. PhosTag-based analysis revealed that the phosphorylated/unphosphorylated PhoP ratio, rather than absolute levels, is the critical determinant of Pho regulon activation under these conditions. Given that PhoR can phosphorylate non-cognate YycF, the response regulator of the essential YycFG system controlling cell wall metabolism. We hypothesized that PhoP phosphorylation in the absence of PhoR may be mediated by YycG. Supporting this, PhoP co- immunoprecipitated with YycG, and in vitro phosphorylation assays confirmed direct phosphorylation of PhoP by YycG. We propose a Pi-stress regulatory model in which CcpA prevents excessive PhoP accumulation, thereby maintaining an appropriate balance between phosphorylated and unphosphorylated PhoP. This regulatory balance prevents aberrant PhoP activation via non-cognate kinases such as YycG in the absence of PhoR. Our findings highlight the interplay between carbon catabolite repression and phosphate starvation responses, and reveal a novel mechanism by which non- cognate phosphorylation contributes to adaptive transcriptional regulation.

molecular biology↗

bioRxiv2025

Exploring Cellular Water Dynamics associated with Potassium Ion Changes Using Magnetic Resonance Imaging

Potassium ions play a critical role in modulating cellular physiology, but their direct effects on water dynamics have not been fully explored. Here, we investigated how elevated potassium ion concentrations ([K]) alter intracellular and extracellular water pools in comparison to hypoosmotic stress, using T2 and magnetization transfer (MT) parameters in a close-packed T-lymphocyte cell pellet model. Our findings reveal that the T2 increase primarily reflects an increase in intracellular free water concentration rather than a mere expansion of cell volume. Notably, [K] elevation produced distinct cell swelling profiles and a smaller relative rise in free water at comparable volumetric changes compared to hypoosmotic stress, highlighting more complex mechanisms than straightforward osmotic effects. While T2 proved sensitive to shifts in intracellular water content, the bound pool increased linearly with cell volume expansion. These results underscore that [K]-driven cell swelling diverges functionally from osmotic- driven cell swelling and demonstrate the viability of MRI-based approaches for probing K-dependent cellular events.

biophysics↗

bioRxiv2024

Direct imaging of neural activity reveals neural circuits via spatiotemporal activation mapping

Two years ago, our group reported direct imaging of neuronal activity (DIANA), a functional magnetic resonance imaging (fMRI) technique that directly detects neuronal activity at high spatiotemporal resolution. In this study, we successfully reproduced the DIANA response in medetomidine-anesthetized mice using forelimb electrical stimulation at 11.7 T. More importantly, we showed that multiple neural circuits can be effectively revealed by DIANA fMRI through spatiotemporal activation mapping. The spatiotemporal activation mapping proposed here utilizes the temporal information of the DIANA response, that is, the time when the DIANA response reaches its peak, which is a unique feature that distinguishes it from the activation mapping method used in existing fMRI. Based on DIANA activation areas, we identified several neural circuits involved in forelimb sensory processing in the somatosensory network, which includes multiple brain regions: ventral posterolateral nucleus of the thalamus (VPL), posteromedial thalamic nucleus (POm), forelimb primary somatosensory cortex (S1FL), secondary somatosensory cortex (S2), primary motor cortex (M1), and secondary motor cortex (M2). Additionally, we also identified a pain-related neural circuit involving brain regions of the anterior cingulate cortex (ACC) and mediodorsal nucleus (MD). Interestingly, the spatiotemporal activation mapping also allowed us to identify subregions with different DIANA response times within the same functional region (e.g., VPL, POm, S1FL, and S2). Our study highlights the potential of DIANA fMRI to advance our understanding of sensory information processing throughout the brain and to provide insight into the spatiotemporal dynamics of brain networks at the level of neural circuits.

neuroscience↗

bioRxiv2024

Detection of changes in membrane potential by magnetic resonance imaging

Membrane potential plays a crucial role in various cellular functions. However, existing techniques for measuring membrane potential are often invasive or have limited recording depth. In contrast, magnetic resonance imaging (MRI) offers noninvasive imaging with desirable spatial resolution over large areas. This study investigates the feasibility of utilizing MRI to detect responses of cultured cells and in vivo rat cortex to membrane potential-modulating ionic solutions by measuring magnetic resonance parameters. Our findings reveal that depolarizing (or hyperpolarizing) ionic solutions increase (or decrease) the T2 relaxation time, while the ratio of bound to free water proton shows the opposite trend. These findings also suggest a potential approach to noninvasively detect changes in membrane potential using MRI.

biophysics↗

bioRxiv2023

Antibody-based immunotherapy targeting FAM19A5 reverses synaptic loss and improves cognitive function in Alzheimer's disease.

IntroductionAlzheimers disease (AD) is characterized by the dysregulation of synaptic balance, with progressive loss of synapses outpacing formation, ultimately leading to cognitive decline. However, the lack of effective strategies for restoring lost synapses poses a major barrier to improving clinical outcomes. MethodsWe developed NS101, a monoclonal antibody targeting FAM19A5, a brain-secreted protein. Its preclinical efficacy in restoring synapses and cognition was evaluated using APP/PS1 and P301S mice. The clinical safety and target engagement of NS101 were examined in human participants. ResultsFAM19A5 binds to LRRC4B, a postsynaptic adhesion molecule, leading to synapse reduction. Blocking this interaction with NS101 normalized the rate of synapse elimination in AD mice. This synaptic rebalancing restored the number and function of synapses, resulting in improved cognition. Systemically administered NS101 facilitated the transport of brain FAM19A5 into the bloodstream. DiscussionTargeting FAM19A5 may hold clinical promise for treating AD by restoring synaptic balance.

neuroscience↗

bioRxiv2023

A neuronal substrate for translating nutrient state and resource density estimations into foraging decisions

Foraging animals must balance the costs of exploring their surroundings with the potential benefits of finding nutritional resources. Each time an animal encounters a food source it must decide whether to initiate feeding or continue searching for potentially better options. Experimental evidence and patch foraging models predict that this decision depends on both nutritional state and the density of available resources in the environment. How the brain integrates such internal and external states to adapt the so-called exploration-exploitation trade-off remains poorly understood. We use video-based tracking to show that Drosophila regulates the decision to engage with food patches based on nutritional state and travel time between food patches, the latter being a measure of food patch density in the environment. To uncover the neuronal basis of this decision process, we performed a neurogenetic silencing screen of more than 400 genetic driver lines with sparse expression patterns in the fly brain. We identified a population of neurons in the central complex that acts as a key regulator of the decision to engage with a food patch. We show that manipulating the activity of these neurons alters the probability to engage, that their activity is modulated by the protein state of the animal, and that silencing these neurons perturbs the ability of the animal to adjust foraging decisions to the flys travel time between food patches. Taken together, our results reveal a neuronal substrate that integrates nutritional state and patch density information to control a specific foraging decision, and therefore provide an important step towards a mechanistic explanation of the cognitive computations that resolve complex cost-benefit trade-offs.

neuroscience↗

bioRxiv2023

Acquired epithelial WNT secretion drives niche independence of developing gastric cancer

Recent studies have shed light on the signaling pathways required for gastric tissue maintenance and how aberrations in these key pathways lead to gastric cancer development. Although it has been shown that the WNT pathway is important for gastric epithelial homeostasis, the identity and source of the responsible canonical WNT ligands remain unknown. Furthermore, it is unclear how gastric cancer acquires WNT niche independence - an important early step in tumorigenesis. Using human and mouse gastric organoids and in vivo mouse models, we found that mesenchymal WNT2B and WNT7B maintain gastric epithelium in homeostasis. Next, mouse genetic studies and single-cell multi-omics analyses revealed that activation of MAPK signaling induces secretion of WNT7B in the epithelium itself. We further confirmed that in human gastric cancer, MAPK pathway activation through HER2 overexpression or copy number gains of WNT2 confers WNT independence. Importantly, the epithelium-intrinsic WNT expression could be therapeutically inhibited. Taken together, our results reveal that normal gastric epithelial turnover relies on WNT ligands secreted by niche mesenchymal cells, while transformation involves acquisition of a WNT secretory phenotype in the epithelium - representing a potential target for therapeutic interventions.

cancer biology↗

bioRxiv2021

Induction of virus-induced gene silencing and in planta validation in cucurbits using the CFMMV-Cm vector

Virus-induced gene silencing (VIGS) has been employed for the high-throughput analysis of endogenous gene function. We developed a CaMV 35S promoter-driven cucumber fruit mottle mosaic virus-Cm vector (pCF93) for the efficient generation of viral transcripts in plants. Using the novel pCF93 vector, we identified genes related to male sterility in watermelon (Citrullus lanatus), which is recalcitrant to genetic transformation. We previously reported reference-based and de novo transcriptomic profiling for the detection of differentially expressed genes between a male fertile line (DAH3615) and its near isogenic male sterile line (DAH3615-MS). Based on the RNA-seq results, we identified 38 de novo-exclusive differentially expressed genes (DEDEGs) that are potentially responsible for male sterility. Partial genes of 200[~]300bp were cloned into pCF93 which was then inoculated into DAH, a small type of watermelon that enables high-throughput screening with a small cultivation area. In this manner, we simultaneously characterized phenotypes associated with the 38 candidate genes in a common-sized greenhouse. Eight out of the 38 gene-silenced plants produced male sterile flowers with abnormal stamens and no pollens. Gene expression levels in flowers were validated via RT-qPCR. Stamen histological sections from male sterile floral buds and mature flowers showed developmental disruption and shrunken pollen sacs. Based on the current findings, we believe that the novel pCF93 vector and our VIGS system facilitate high-throughput analysis for the study of gene function in watermelons. One sentence summaryThe CaMV 35S promoter-driven cucumber fruit mottle mosaic virus-Cm vector (pCF93) facilitates large-scale validation of male sterility-related gene functions in watermelon.

plant biology↗

bioRxiv2021

In vivo direct imaging of neuronal activity at high temporo-spatial resolution

There has been a longstanding demand for noninvasive neuroimaging methods capable of detecting neuronal activity at both high temporal and spatial resolution. Here, we propose a novel method that enables Direct Imaging of Neuronal Activity for functional MRI (termed DIANA-fMRI) that can dynamically image spiking activity in milliseconds precision, while retaining the original benefit of high spatial resolution of MRI. DIANA-fMRI was demonstrated through in vivo mice brain imaging at 9.4 T applying electrical whisker-pad stimulation, directly imaging the spiking activity as well as capturing its sequential propagation along the thalamocortical pathway, as further confirmed through in vivo spike recording and optogenetics. DIANA-fMRI will open up new avenues in brain science by providing a deeper understanding of the brains functional organization including neural networks.

neuroscience↗

bioRxiv2020

Quality threshold evaluation of Sanger confirmation for results of whole exome sequencing in clinically diagnostic setting

BackgroundWith the ability to simultaneously sequence more than 5,000 disease-associated genes, next-generation sequencing (NGS) has replaced Sanger sequencing as the preferred method in the diagnostic field at the laboratory level. However, Sanger sequencing has been used routinely to confirm identified variants prior to reporting results. This validation process causes a turnaround time delay and cost increase. Thus, this study aimed to set a quality threshold that does not require Sanger confirmation by analyzing the characteristics of identified variants from whole exome sequencing (WES). MethodsOur study analyzed data on a total of 694 disease-causing variants from 578 WES samples that had been diagnosed with suspected genetic disease. These samples were sequenced by Novaseq6000 and Exome Research Panel v2. All 694 variants (513 single-nucleotide variants (SNVs) and 181 indels) were validated by Sanger sequencing. ResultsA total of 693 variants included 512 SNVs and 181 indels from 578 patients and 367 genes. Five hundred seven heterozygous SNVs with at > 250 quality score and > 0.3 allele fraction were 100% confirmed by Sanger sequencing. Five heterozygous variants and one homozygous variant were not confirmed by Sanger sequencing, which showed 98.8% accuracy. There were 146 heterozygous variants and 35 homozygous variants among 181 indels, of which 11 heterozygous variants were not confirmed by Sanger sequencing (93.9% accuracy). Five non-confirmed variants with high quality were not identified on the ram .bam file. ConclusionOur results indicate that Sanger confirmation is not necessary for exome-derived SNVs with > 250 quality score and 0.3 > allele fraction set to an appropriate quality threshold. Indels or SNVs that do not meet the quality threshold should be reviewed by raw .bam file and Sanger confirmation should be performed to ensure accurate reporting.

genetics↗

bioRxiv2020

Generation of tonsil organoids as an ex vivo model for SARS-CoV-2 infection

Palatine tonsil (hereinafter referred to as "tonsil") plays role in the immune systems first line of defense against foreign pathogens. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic since the infection was first reported in China in December 2019. The aim of this study was to establish tonsil epithelial cell-derived organoids and to examine their feasibility as an ex vivo model for SARS-CoV-2 infection. Using an optimized protocol, we achieved 3D tonsil organoid culture from human tonsil tissue that reflects the distinctive characteristics of the tonsil epithelium, such as its cellular composition, histologic properties, and molecular biological features. Notably, we verified that SARS-CoV-2 can infect tonsil organoids with a robust replication efficiency. Furthermore, treatment with remdesivir, an antiviral agent, effectively protected them from viral infection. Therefore, tonsil organoids could be available for investigation of SARS-CoV-2 infection-mediated pathology and for preclinical screening of novel antiviral drug candidates. One-sentence SummaryThis study established tonsil epithelial cell-derived organoids and demonstrated their feasibility as an ex vivo model for SARS-CoV-2 infection.

microbiology↗

bioRxiv2019

Unveiling the crucial role of type IV secretion system and motility of Helicobacter pylori in IL-1β production via NLRP3 inflammasome activation in neutrophils

Helicobacter pylori is a gram-negative, microaerophilic, and spiral-shaped bacterium and causes gastrointestinal diseases in human. IL-1{beta} is a representative cytokine produced in innate immune cells and is considered to be a key factor in the development of gastrointestinal malignancies. However, the mechanism of IL-1{beta} production by neutrophils during H. pylori infection is still unknown. We designed this study to identify host and bacterial factors involved in regulation of H. pylori-induced IL-1{beta} production in neutrophils. We found that H. pylori-induced IL-1{beta} production is abolished in NLRP3-, ASC-, and caspase-1/11-deficient neutrophils, suggesting essential role for NLRP3 inflammasome in IL-1{beta} response against H. pylori. Host TLR2, but not TLR4 and Nod2, was also required for transcription of NLRP3 and IL-1{beta} as well as secretion of IL-1{beta}. H. pylori lacking cagL, a key component of the type IV secretion system (T4SS), induced less IL-1{beta} production in neutrophils than did its isogenic WT strain, whereas vacA and ureA were dispensable. Moreover, T4SS was involved in caspase-1 activation and IL-1{beta} maturation in H. pylori-infected neutrophils. We also found that FlaA is essential for H. pylori-mediated IL-1{beta} production in neutrophils, but not dendritic cells. TLR5 and NLRC4 were not required for H. pylori-induced IL-1{beta} production in neutrophils. Instead, bacterial motility is essential for the production of IL-1{beta} in response to H. pylori. In conclusion, our study shows that host TLR2 and NLRP3 inflammasome and bacterial T4SS and motility are essential factors for IL-1{beta} production by neutrophils in response to H. pylori.\n\nIMPORTANCEIL-1{beta} is a representative pro-inflammatory cytokine and is considered to be a central host factor for the development of gastric cancers. Although neutrophils have been considered to be involved in H. pylori-induced gastric inflammation, the underlying mechanism by which H. pylori triggers IL-1{beta} production in neutrophils remains to be defined. In this study, our data suggested a critical role for the host TLR2 and NLRP3 inflammasome in IL-1{beta} production by neutrophil during H. pylori infection. Moreover, we found the bacterial factors, T4SS and FlaA, to be essential for IL-1{beta} production and NLRP3 activation during the course of H. pylori infection. Our current findings provide detailed molecular genetic mechanisms associated with IL-1{beta} production in neutrophils in response to H. pylori infection, which can serve as innovative anti-inflammatory targets to reduce H. pylori-induced gastric malignancies.

immunology↗

bioRxiv2019

High diagnostic yield and clinical utility of WES for patients with undiagnosed genetic disorder by automating variant interpretation

PurposeEVIDENCE, an automated interpretation system, has been developed to facilitate the entire process of whole exome sequencing (WES) analyses. This study investigated the diagnostic yield of EVIDENCE in patients suspected genetic disorders. MethodsDNA from 330 probands (age range, 0-68 years) with suspected genetic disorders were subjected to WES. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments. ResultsThe average number of overlapping organ categories per patient was 4.5 {+/-} 5.0. EVIDENCE reported a total 244 variants in 215 (65.1%) of the 330 probands. After clinical reassessment and/or family member testing, 196 variants were identified in 171 probands (51.8%), including 115 novel variants. These variants were confirmed as being responsible for 146 genetic disorders. One hundred-seven (54.6%) of the 196 variants were categorized as pathogenic or likely pathogenic before, and 146 (74.6%) after, clinical assessment and/or family member testing. Factors associated with a variant being confirmed as causative include rules, such as PVS1, PS1, PM1, PM5, and PP5, and similar symptom scores between that variant and a patients phenotype. ConclusionThis new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 51% improvement in diagnostic yield.

genetics↗