Biology subjects

Simmons, S.

Publications and source records attributed to Simmons, S..

17 recordsLinked to original sources

bioRxiv2026

Lung microvascular rarefaction impairs pulmonary gas exchange and exacerbates heart failure with preserved ejection fraction

BackgroundDyspnea and exercise intolerance are the primary clinical symptoms of heart failure. Heart failure patients experience frequent hypoxemic episodes, yet underlying mechanisms and relevance remain poorly understood. In a cohort of heart failure patients and multiple animal models, we identify pulmonary capillary rarefaction driven by excessive autophagy in endothelial cells as a novel mechanism of hypoxemia and cardiac disease progression. MethodsA cohort of heart failure with preserved ejection fraction (HFpEF) patients was analyzed for parameters of left ventricular (LV) dysfunction and pulmonary gas exchange. Morphological and cellular mechanisms of impaired pulmonary oxygenation were assessed in three animal models of heart failure, namely two HFpEF models, SU5416-treated ZSF1 obese rats and high fat diet/L-NAME treated mice, and in rats subjected to aortic banding. Lung microvascular rarefaction was quantified by micro-computed tomography, stereology, flow cytometry and dye efflux. Cellular mechanisms of capillary loss were analyzed by single-cell transcriptomics, electron microscopy and immunofluorescence, and in mice with endothelial-specific deletion of the autophagy gene Atg7 (Atg7EN-KO). ResultsIn 234 HFpEF patients, advancing NYHA class was associated with progressive worsening of arterial oxygen saturation at rest and during exercise and a reduced lung diffusing capacity. Impaired gas diffusion correlated with indices of LV diastolic dysfunction. Impaired oxygenation and reduced exercise capacity were similarly evident in animal models of left heart disease, which showed a distinct loss of pulmonary microvessels and capillaries. Lung microvascular endothelial cells in HFpEF showed characteristics of increased autophagic flux and apoptosis. Relative to their wild type HFpEF controls, Atg7EN-KO mice had less capillary loss, restored normoxemia, improved exercise tolerance, and mitigated LV diastolic dysfunction. Additional studies in HFpEF mice corroborated the functional relevance of impaired gas exchange for the progression of left heart disease by demonstrating that additional hypoxia aggravated, whereas moderate hyperoxia improved LV function. ConclusionOur findings identify pulmonary microvascular rarefaction as a novel pathomechanism in heart failure that i) contributes to dyspnea and exercise intolerance, ii) impairs pulmonary gas exchange and iii) accelerates LV disease progression. Strategies targeting this axis such as moderate oxygen therapy may mitigate cardiopulmonary morbidity in heart failure. Clinical Trial RegistrationRegistered in the DRKS (Deutsches Register fur klinische Studien) as trial# DRKS00032974 at https://drks.de/search/en/trial/DRKS00032974.

physiology↗

bioRxiv2025

Myeloid cell recruitment propels right ventricular dysfunction in HFpEF via sterile inflammation.

BackgroundIn contrast to what has already been shown in HFpEF associated left ventricular (LV) diastolic dysfunction, leukocytes role in frequently occurring right ventricular dysfunction (RVD) secondary to HFpEF are so far missing, partially due to the lack of suitable small animal models. Here, we follow a translational research approach by establishing a murine HFpEF model developing manifest RVD and analyzed human HFpEF cohorts to study the mechanistic link between leukocytes and RVD in HFpEF. Methods8-week-old male and female C57BL/6J or Cx3cr1CreER/+R26tdTomato/+ mice were divided into four experimental groups: i) chow, ii) HFpEF (N[{omega}]-nitro-l-arginine methyl ester (L-NAME), 60% high-fat diet), iii) chronic hypoxia (10% O2) and iv) HFpEF and hypoxia (RV-HFpEF) to assess bi-ventricular function and myeloid cell dynamics. To test whether myeloid cells are causally involved in the development of RV remodeling in HFpEF, we additionally treated RV-HFpEF mice with the colony stimulating factor 1 receptor inhibitor PLX-5622 (PLX) to deplete myeloid cells. After 12 weeks, all experimental groups were subjected to transthoracic echocardiography, invasive hemodynamics or flow cytometry. ResultsRV-HFpEF resulted in LV diastolic dysfunction indicated by increased E/E ratio, reduced global longitudinal peak strain, smaller end-diastolic diameters and increased isovolumetric relaxation time compared to chow. RV-HFpEF animals developed RV hypertrophy and RVD evident as increased Fultons index and collagen content as well as elevated RV systolic pressures (RVSPs) and reduced tricuspid annular plane systolic excursion, respectively. Flow cytometric analyses revealed elevated total leukocyte, monocyte, and macrophage counts in RV tissue of RV-HFpEF compared to chow or LV tissue from RV-HFpEF animals. These data were confirmed by unbiased proteomic analyses of RV tissue from RV-HFpEF mice, demonstrating increased abundance of proteins involved in activation of the innate immune system, macrophage chemotaxis, cell adhesion and extracellular matrix organization when compared to LV tissue or other experimental groups. Fate mapping experiments revealed that recruited monocyte-derived macrophages became the main source of total cardiac macrophages in RV tissue from RV-HFpEF mice. Depletion of myeloid cells was associated with rescued RVSP profiles compared to RV-HFpEF control mice. In HFpEF patients, RV dilation was associated with an increased percentage of circulating monocytes. In RV biopsies from HFpEF patients, we found increased expression of adhesion molecules, fibrotic markers and inflammatory transcripts. ConclusionWe demonstrate that dysregulated myeloid cell dynamics are associated with, and directly contribute to, the pathogenesis of HFpEF-associated RVD in humans and mice. Clinical PerspectiveWhat is new: O_LIWe explore myeloid cell dynamics in a novel three-hit experimental HFpEF mouse model with RV hypertrophy, RV end-systolic pressure and RV dysfunction. C_LIO_LIIn this model, RV dysfunction was associated with macrophage expansion, monocyte recruitment and extracellular matrix deposition, whilst macrophage depletion partly reversed these changes and rescued RV hemodynamics. C_LIO_LIHFpEF patients with RV dilation or RV dysfunction exhibit unique leukocyte dynamics and inflammatory profiles when compared to HFpEF patients with normal RV function or diameters. C_LI Clinical implications: O_LIThere exists a major clinical discrepancy between high incidence of RV dysfunction associated to HFpEF and a lack of targeted treatment strategies. C_LIO_LIOur novel three-hit mouse model recapitulates many features of the clinical scenario of HFpEF patients with RV dysfunction, therefore representing an important step towards systematic testing and development of targeted treatment options. C_LIO_LISterile inflammation and dysregulation of innate immune cells may be suitable targets for therapeutic interventions against RV dysfunction in HFpEF. C_LI

physiology↗

bioRxiv2025

A Case Study Leveraging Angler Reported Data For Whirling Disease Monitoring

The Bow River (Alberta, Canada) has a well-documented decline in its rainbow trout fishery, with several stressors attributed to this decline including whirling disease (WD). This study evaluated whether anglers could detect recruitment failure in WD-impacted areas of the Bow River drainage using a smartphone app-based citizen science initiative. Anglers reported age 1 and 2 rainbow and cutthroat trout identified by size distribution, estimated from a provincial database, across 4 sub-watersheds with varying densities of Myxobolus cerebralis actinospores (TAMs), a known predictor of WD severity. TAM densities ranged from undetectable (0 TAMs/L - Waiparous Creek) to moderate (< 0.01 TAMs/L - Sheep and Highwood Rivers) and high (> 0.01 TAMs/L - Jumpingpound Creek). No fish were captured in Jumpingpound Creek over 20.2 angling hours. The Highwood and Sheep Rivers had catch rates of 0.4 and 0.2 age 1 and 2 trout per hour over 30.6 and 27.7 hours, respectively. Waiparous Creek, where WD was absent, had a significantly higher catch rate of 2.2 trout per hour over 20.3 hours. These findings suggest that self-reported angler data can potentially help identify recruitment losses in WD-impacted areas, demonstrating a novel application of citizen science in fisheries research.

ecology↗

bioRxiv2025

Inflammatory disease microbiomes share a functional pathogenicity predicted by C-reactive protein

We examine disease-specific and cross-disease functions of the human gut microbiome by colonizing germ-free mice, at risk for inflammatory arthritis, colitis, or neuroinflammation, with over 100 human fecal microbiomes from subjects with rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, ulcerative colitis, Crohns disease, or colorectal cancer. We find common inflammatory phenotypes driven by microbiomes from individuals with intestinal inflammation or inflammatory arthritis, as well as distinct functions specific to microbiomes from multiple sclerosis patients. Inflammatory disease in mice colonized with human microbiomes correlated with systemic inflammation, measured by C-reactive protein, in the human donors. These cross-disease patterns of human microbiome pathogenicity mirror features of the inflammatory diseases, including therapeutic targets and the presence or absence of systemic inflammation, suggesting shared and disease-specific mechanisms by which the microbiome is shaped and drives pathogenic inflammatory responses.

immunology↗

bioRxiv2024

Pneumonia induced rise in glucagon promotes endothelial damage and vascular thrombogenicity

BackgroundRecent studies have demonstrated a link between respiratory infections and increased short-term risk of cardiovascular disease (CVD). However, the molecular mechanisms underlying the increased cardiovascular risk after respiratory infections are only poorly understood. Here, we aimed to decipher pathophysiological circuits of pneumonia associated CVD in experimental models of bacterial pneumonia and vascular injury. MethodsC57BL/6J mice were exposed to intranasal inoculation with either Streptococcus pneumoniae (S. pneumoniae) serotype 4 (pneumonia group) or phosphate buffered saline (PBS) (control group). 24 hours post infectionem (p.i.) mice were treated with antibiotics until the end of the study. On day 7 p.i. carotid artery injury (CI) was induced by electric stimulation and vascular repair was analyzed 3 days after injury. Plasma proteomic analyses were performed by Olink Bioscience. Primary human aortic endothelial cells (HAECs) were used to study alterations of the endothelial functional properties, bioenergetic state and thrombogenic potential in vitro. Intravital fluorescence microscopy equipped with video recording was applied to measure thrombus formation in real-time. ResultsBacterial pneumonia impaired repair capacity of the endothelium after vascular injury. Proteomic analyses revealed significantly higher plasma levels of glucagon in mice after recovery from pneumonia relative to controls, which was further confirmed by ELISA detecting glucagon. Mechanistically, we found that glucagon impaired mitochondrial bioenergetics and migratory potential in HAECs and induced an inflammatory response. Moreover, glucagon fostered vascular thrombogenicity as demonstrated by increased thrombocyte adhesion to HAECs and accelerated carotid artery thrombus formation in vivo. Acute application of the glucagon-like peptide-1 receptor (GLP1-R) agonist liraglutide to lower blood glucagon levels, restored vascular repair potential and attenuated vascular thrombogenicity in mice with pneumonia. ConclusionsOur findings reveal a novel mechanism that associates elevated circulatory glucagon levels to dysfunctional endothelium and increased vascular thrombogenicity, suggesting glucagon signaling as a potential therapeutic target to prevent pneumonia-induced cardiovascular events. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/592488v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1dab59eorg.highwire.dtl.DTLVardef@1c9a033org.highwire.dtl.DTLVardef@34a566org.highwire.dtl.DTLVardef@56e33d_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

Neuronal-class specific molecular cues drive differential myelination in the neocortex

In the neocortex, oligodendrocytes produce distinct amounts of myelin in each cortical layer and along the axons of individual neuron types. Here we present a comprehensive single-cell molecular map of mouse cortical oligodendrocytes across different cortical layers and stages of myelination, spanning the initiation of cortical myelination into adulthood. We apply this dataset to show that neuron-class specific signals drive oligodendrocyte maturation and differential myelination across cortical layers. We find that each layer contains a similar compendium of oligodendrocyte classes, indicating that oligodendrocyte heterogeneity cannot explain layer-specific myelination. To evaluate whether neuronal diversity drives differential myelination across cortical layers, we generated a predicted ligand-receptor interactome between projection neuron types and oligodendrocyte states, across cortical layers and time. In vivo functional testing identified Fgf18, Ncam1, and Rspo3 as novel, neuron-derived pro-myelinating signals. Our results highlight neuron-class-dependent control of myelin distribution in the neocortex.

neuroscience↗

bioRxiv2023

Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), present in up to 80% of patients and leading to a diminished quality of life. We have developed a model of lupus-like cognitive impairment which is initiated when anti-DNA, anti-N-methyl D-aspartate receptor (NMDAR) cross-reactive antibodies, which are present in 30% of SLE patients, penetrate the hippocampus. This leads to immediate, self-limited excitotoxic death of CA1 pyramidal neurons followed by a significant loss of dendritic arborization in the remaining CA1 neurons and impaired spatial memory. Both microglia and C1q are required for dendritic loss. Here we show that this pattern of hippocampal injury creates a maladaptive equilibrium that is sustained for at least one year. It requires HMGB1 secretion by neurons to bind RAGE, a receptor for HMGB1 expressed on microglia, and leads to decreased expression of microglial LAIR-1, an inhibitory receptor for C1q. The angiotensin converting enzyme (ACE) inhibitor captopril, which can restore a healthy equilibrium, microglial quiescence, and intact spatial memory, leads to upregulation of LAIR-1. This paradigm highlights HMGB1:RAGE and C1q:LAIR-1 interactions as pivotal pathways in the microglial-neuronal interplay that defines a physiologic versus a maladaptive equilibrium.

immunology↗

bioRxiv2023

A single-cell map of antisense oligonucleotide activity in the brain

Antisense oligonucleotides (ASOs) dosed into cerebrospinal fluid (CSF) distribute broadly throughout the brain and hold the promise of treating myriad brain diseases by modulating RNA. CNS tissue is not routinely biopsied in living individuals, leading to reliance on CSF biomarkers to inform on drug target engagement. Animal models can link CSF biomarkers to brain parenchyma, but our understanding of how individual cells contribute to bulk tissue signal is limited. Here we employed single nucleus transcriptomics on tissue from mice treated with RNase H1 ASOs against Prnp and Malat1 and macaques treated with an ASO against PRNP. Activity was observed in every cell type, though sometimes with substantial differences in magnitude. Single cell RNA count distributions implied target suppression in every single sequenced cell, rather than intense knockdown in only some cells. Duration of action up to 12 weeks post-dose differed across cell types, being shorter in microglia than in neurons. Suppression in neurons was generally similar to, or more robust than, the bulk tissue. In macaques, PrP in CSF was lowered 40% in conjunction with PRNP knockdown across all cell types including neurons, arguing that a CSF biomarker readout is likely to reflect disease-relevant cells in a neuronal disorder.

neuroscience↗

bioRxiv2022

A machine learning based image classification method to estimate fish sizes from images without a specified reference object

Most fish populations around the world are unassessed and their status is unknown. Size based methods could provide fast and transparent assessments, but they require information on fish sizes. Citizen science programs, social media and smart phone applications generate millions of georeferenced fish images globally. Machine learning based fish species and size identification could help turn these images into valuable data for population status assessments. We present a machine learning, image classification based method to identify fish size classes from photos of anglers holding fish. To train the model we group images into ten 5-10 cm size classes, similar to classes used in underwater visual fish surveys. The model was trained using 2602 images from angler citizen science platforms MyCatch and FishSizeProject. Although the number of images was limited, the model achieved an overall accuracy of ~50%. Importantly, the misidentification of size classes was consistent across 20 separate model training rounds, each conducted with an independent, random allocation of images for training and test datasets. Our method suggests that photo based fish size class identification is feasible, and that prediction uncertainty should be incorporated into subsequent analysis, as it is done with fish ageing errors in fisheries stock assessments.

ecology↗

bioRxiv2022

The effect of background noise and its removal on the analysis of single-cell expression data

BACKGROUNDIn droplet-based single-cell and single-nucleus RNA-seq experiments, not all reads associated with one cell barcode originate from the encapsulated cell. Such background noise is attributed to spillage from cell-free ambient RNA or barcode swapping events. Here, we characterize this background noise exemplified by three single-cell RNA-seq (scRNA-seq) and two single-nucleus RNA-seq (snRNA-seq) replicates of mouse kidney cells. For each experiment, kidney cells from two mouse subspecies were pooled, allowing to identify cross-genotype contaminating molecules and estimate the levels of background noise. RESULTSWe find that background noise is highly variable across replicates and individual cells, making up on average 3-35% of the total counts (UMIs) per cell and show that this has a considerable impact on the specificity and detectability of marker genes. In search of the source of background noise, we find that expression profiles of cell-free droplets are very similar to expression profiles of cross-genotype contamination and hence that the majority of background molecules originates from ambient RNA. Finally, we use our genotype-based estimates to evaluate the performance of three methods (CellBender, DecontX, SoupX) that are designed to quantify and remove background noise. We find that CellBender provides the most precise estimates of background noise levels and also yields the highest improvement for marker gene detection. By contrast, clustering and classification of cells are fairly robust towards background noise and only small improvements can be achieved by background removal that may come at the cost of distortions in fine structure. CONCLUSIONOur findings help to better understand the extent, sources and impact of background noise in single-cell experiments and provide guidance on how to deal with it.

bioinformatics↗

bioRxiv2022

A scalable open-source framework for machine learning based image collection, annotation and classification: a case study for automatic fish species identification

Citizen science platforms, social media and multiple smart phone applications enable collection of large amounts of georeferenced images. This provides a huge opportunity in biodiversity and ecological research, but also creates challenges for efficient data handling and processing. Recreational and small-scale fisheries is one of the fields that could be revolutionised by efficient, widely accessible and machine learning based processing of georeferenced images. The majority of non-commercial inland and coastal fisheries are considered data poor and are rarely assessed, yet they provide multiple societal benefits and can have large ecological impacts. Given that large quantities of fish observations and images are being collected by fishers every day, artificial intelligence (AI) and computer vision applications offer a great opportunity to improve data collection, automate analyses and inform management. Yet, to date, many AI image analysis applications in fisheries are focused on the commercial sector and are not publicly available for community use. In this study we present an open-source modular framework for large scale image storage, handling, annotation and automatic classification, using cost- and labour-efficient methodologies. The tool is based on TensorFlow Lite Model Maker library and includes data augmentation and transfer learning techniques, applied to different convolutional neural network models. We demonstrate the implementation of this framework in an example case study for automatic fish species identification from images taken through a recreational fishing smartphone application. The framework presented here is highly customisable for further advancement and community based image collection and annotation.

ecology↗

bioRxiv2022

A live attenuated vaccine confers superior mucosal and systemic immunity to SARS-CoV-2 variants

Vaccines are a cornerstone in COVID-19 pandemic management. Here, we compare immune responses to and preclinical efficacy of the mRNA vaccine BNT162b2, an adenovirus-vectored spike vaccine, and the live-attenuated-virus vaccine candidate sCPD9 after single and double vaccination in Syrian hamsters. All regimens containing sCPD9 showed superior efficacy. The robust immunity elicited by sCPD9 was evident in a wide range of immune parameters after challenge with heterologous SARS-CoV-2 including rapid viral clearance, reduced tissue damage, fast differentiation of pre-plasmablasts, strong systemic and mucosal humoral responses, and rapid recall of memory T cells from lung tissue. Our results demonstrate that use of live-attenuated vaccines may offer advantages over available COVID-19 vaccines, specifically when applied as booster, and may provide a solution for containment of the COVID-19 pandemic.

immunology↗

bioRxiv2021

Blast-induced mild traumatic brain injury alterations of corticotropin-releasing factor neuronal activity in the mouse hypothalamic paraventricular nucleus

Blast-induced mild traumatic brain injury (mbTBI) is the most common cause of TBI in US service members and veterans. Those exposed to TBI are at greater risk of developing neuropsychiatric disorders such as posttraumatic stress disorder, anxiety and depressive disorders, and substance use disorders following TBI [1, 2]. Previously, we have demonstrated that mbTBI increases anxiety-like behaviors in mice and dysregulates the stress at the level of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN). To expand on how mTBI may dysregulate the stress axis centrally, here PVN CRF neuronal activity was evaluated using whole cell-patch clamp recordings in hypothalamic slices from sham and mbTBI adult male CRF:tdTomato mice 7 days post-injury. We found that mbTBI generally did not affect the neuronal excitability and intrinsic membrane properties of PVN CRF neurons; this injury selectively increased the frequency of spontaneous neuronal firing of PVN CRF neurons localized to the dorsal PVN (dPVN) but not ventral PVN (vPVN). Consistently, mbTBI-induced dPVN CRF hyperactivity was associated with pre- and post-synaptic depression of spontaneous GABAergic transmission onto dPVN CRF neurons suggesting that mbTBI-induced GABAergic synaptic dysfunction may underlie dPVN CRF neuronal hyperactivity and increases in dPVN CRF signaling. The present results provide the first evidence for mbTBI-induced alterations in PVN CRF neuronal activity and GABAergic synaptic function that could mediate hypothalamic CRF dysregulation following mbTBI contributing to stress psychopathology associated with blast injury.

neuroscience↗

bioRxiv2020

Privacy-preserving biomedical database queries with optimal privacy-utility trade-offs

Sharing data across research groups is an essential driver of biomedical research. In particular, biomedical databases with interactive query-answering systems allow users to retrieve information from the database using restricted types of queries (e.g. number of subjects satisfying certain criteria). While these systems aim to facilitate the sharing of aggregate biomedical insights without divulging sensitive individual-level data, they can still leak private information about the individuals in the database through the query answers. Existing strategies to mitigate such risks either provide insufficient levels of privacy or greatly diminish the usefulness of the database. Here, we draw upon recent advances in differential privacy to introduce privacy-preserving query-answering mechanisms for biomedical databases that provably maximize the expected utility of the system while achieving formal privacy guarantees. We demonstrate the accuracy improvement of our methods over existing approaches for a range of use cases, including count, membership, and association queries. Notably, our new theoretical results extend the proof of optimality of the underlying mechanism, previously known only for count queries with symmetric utility functions, to asymmetric utility functions needed for count queries in cohort discovery workflows as well as membership queries--a core functionality of the Beacon Project recently launched by the Global Alliance for Genomics and Health (GA4GH). Our work presents a path towards biomedical query-answering systems that achieve the best privacy-utility trade-offs permitted by the theory of differential privacy.

bioinformatics↗

bioRxiv2019

Spatiotemporal dynamics of RNA virus diversity in a phyllosphere microbial community

Although metagenomics reveals that natural virus communities harbor vast genetic diversity, the spatiotemporal dynamics of viral diversity in the wild are seldom tested, especially across small geographic scales. This problem is usefully examined in the above-ground phyllosphere, because terrestrial plants are frequently infected by taxonomically-diverse RNA viruses, whose elevated mutation rates generate abundant allele diversity. Here, we studied the problem by comparative analysis of RNA virus samples over time from three spatially-separated patches of a common perennial legume, white clover (Trifolium repens L.), growing in a grassy lawn in Woods Hole Village (Falmouth, MA, USA). We predicted that clover samples would show similarly high levels of virus species (alpha) diversity across space, but differing among-patch diversity of non-dominant virus taxa over time (4 samples spanning 6 weeks). Results showed that recognizable alpha diversity in clover patches was consistently dominated by RNA virus family Alphaflexiviridae across space, but that all patches showed inconsistent spatiotemporal presence of a diversity of minority virus families. Also, we observed that white clover mosaic virus (WClMV) dominated all patches across space and time. The high coverage of WClMV fostered an haplotype analysis, which revealed that two strains of the virus consistently infected clover plants during the 6-week period.

microbiology↗

bioRxiv2017

Genomic sequencing identifies secondary findings in a cohort of parent study participants

PURPOSEClinically relevant secondary variants were identified in parents enrolled with a child with developmental delay and intellectual disability.\n\nMETHODSExome/genome sequencing and analysis of 789 unaffected parents was performed.\n\nRESULTSPathogenic/likely pathogenic variants were identified in 21 genes within 25 individuals (3.2%), with 11 (1.4%) participants harboring variation in a gene defined as clinically actionable by the ACMG. Of the 25 individuals, five carried a variant consistent with a previous clinical diagnosis, thirteen were not previously diagnosed but had symptoms or family history with probable association with the detected variant, and seven reported no symptoms or family history of disease. A limited carrier screen was performed yielding 15 variants in 48 (6.1%) parents. Parents were also analyzed as mate-pairs to identify cases in which both parents were carriers for the same recessive disease; this led to one finding in ATP7B. Four participants had two findings (one carrier and one non-carrier variant). In total, 71 of the 789 enrolled parents (9.0%) received secondary findings.\n\nCONCLUSIONWe provide an overview of the rates and types of clinically relevant secondary findings, which may be useful in the design, and implementation of research and clinical sequencing efforts to identify such findings.

genomics↗

bioRxiv2016

Genomic diagnosis for children with intellectual disability and/or developmental delay

BackgroundDevelopmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios.\n\nMethodsWhole exome sequences (WES) were generated for 365 individuals (127 affected) and whole genome sequences (WGS) were generated for 612 individuals (244 affected).\n\nResultsPathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected 1st degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS, and 4.7% of families with a negative result, eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGAP.\n\nConclusionOur data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.

genomics↗