7 research outputs found
Characterization of long COVID temporal sub-phenotypes by distributed representation learning from electronic health record data: a cohort studyResearch in Context
Summary: Background: Characterizing Post-Acute Sequelae of COVID (SARS-CoV-2 Infection), or PASC has been challenging due to the multitude of sub-phenotypes, temporal attributes, and definitions. Scalable characterization of PASC sub-phenotypes can enhance screening capacities, disease management, and treatment planning. Methods: We conducted a retrospective multi-centre observational cohort study, leveraging longitudinal electronic health record (EHR) data of 30,422 patients from three healthcare systems in the Consortium for the Clinical Characterization of COVID-19 by EHR (4CE). From the total cohort, we applied a deductive approach on 12,424 individuals with follow-up data and developed a distributed representation learning process for providing augmented definitions for PASC sub-phenotypes. Findings: Our framework characterized seven PASC sub-phenotypes. We estimated that on average 15.7% of the hospitalized COVID-19 patients were likely to suffer from at least one PASC symptom and almost 5.98%, on average, had multiple symptoms. Joint pain and dyspnea had the highest prevalence, with an average prevalence of 5.45% and 4.53%, respectively. Interpretation: We provided a scalable framework to every participating healthcare system for estimating PASC sub-phenotypes prevalence and temporal attributes, thus developing a unified model that characterizes augmented sub-phenotypes across the different systems. Funding: Authors are supported by National Institute of Allergy and Infectious Diseases, National Institute on Aging, National Center for Advancing Translational Sciences, National Medical Research Council, National Institute of Neurological Disorders and Stroke, European Union, National Institutes of Health, National Center for Advancing Translational Sciences
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Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy
Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)–associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype.
This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy.
All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family.
Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings
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Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly
Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease.
We identify five unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models.
Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles.
Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.
Huang et al. report the first functional validation of candidate pathological variants in RBBP5. We present three truncating p.(K244Nfs*6), p.(W254*), p.(R307*) and two missense p.(T232I), p.(E296D) variants found de novo in affected individuals sharing phenotypes including microcephaly and short stature. RBBP5 is a core member of the COMPASS complex responsible for H3 lysine 4 methylation to activate developmental target genes (COMPASS complex adapted from Namitz et al., 2023). Differentiation of neural stem cells in humans and neuroblasts in Drosophila is conserved allowing for the study of neural development in the fly model organism (neural stem cell/neuroblast differentiation diagram adapted from Kim and Hirth, 2009). We used overexpression and rescue experiments to characterize the missense variants in the fly. Neural progenitor populations were evaluated in the larval brain and tissue specific phenotypes were quantified using adult eye and wing morphology studies. We identify that the truncating and missense variants are loss-of-function alleles. As additional patients are identified, the full phenotypic spectrum of RBBP5-related disorders will be elucidated. Created with Biorender.com. [Display omitted
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Cohort expansion and genotype-phenotype analysis of RAB11A-associated neurodevelopmental disorder
Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11
Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants.We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality.Patients with variants in GDF11 presented with craniofacial (5/6), vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6), and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) allele whereas the missense variants in our cohort are partial LOF variants.GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues
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De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling
Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants.
We describe a neurodevelopmental disorder associated with de novo gain-of-function variants in PIP5KIγ kinase. The variants cause perturbed endosomal function resulting from increased production of phosphatidylinositol 4,5 bisphosphate and enhanced association of F-actin at endosomes. Moreover, mutant zebrafish larvae recapitulate the phenotypes observed in affected individuals from our cohort