Hakon Hakonarson

PurposeRNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease. Case reports have also implicated specific variants in RNF213 with an early-onset form of moyamoya disease with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations.MethodsPatients were identified through reanalysis of exome sequencing data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient-derived fibroblasts.ResultsWe identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the Really Interesting New Gene (RING) domain. Individuals …

PurposePersistent human papillomavirus infection (PHPVI) causes cutaneous, anogenital, and mucosal warts. Cutaneous warts include common warts, Treeman syndrome, and epidermodysplasia verruciformis, among others. Although more reports of monogenic predisposition to PHPVI have been published with the development of genomic technologies, genetic testing is rarely incorporated into clinical assessments. To encourage broader molecular testing, we compiled a list of the various monogenic etiologies of PHPVI.MethodsWe conducted a systematic literature review to determine the genetic, immunological, and clinical characteristics of patients with PHPVI.ResultsThe inclusion criteria were met by 261 of 40,687 articles. In 842 patients, 83 PHPVI-associated genes were identified, including 42, 6, and 35 genes with strong, moderate, and weak evidence for causality, respectively. Autosomal recessive …

Study Objectives To identify genetic susceptibility variants in pediatric obstructive sleep apnea in European American and African American children. Methods A phenotyping algorithm using electronic medical records was developed to recruit cases with OSA and control subjects from the Center for Applied Genomics at Children’s Hospital of Philadelphia (CHOP). Genome-wide association studies (GWAS) were performed in pediatric OSA cases and control subjects with European American (EA) and African American (AA) ancestry followed by meta-analysis and sex stratification. Results The algorithm accrued 1486 subjects (46.3% European American, 53.7% African American). We identified genomic loci at 1p36.22 and 15q26.1 that associated with OSA risk in EA and AA, respectively. We also revealed a shared risk locus at 18p11.32 (rs114124196, p …

Methods and uses for diagnosing and treating anxiety disorders are encompassed, wherein diagnosis and treatment may be based upon an assessment of genetic alterations in metabotropic glutamate receptor (mGluR) network genes and wherein treatment is with nonspecific activators of mGluRs such as fasoracetam.

CD8+ T cell dysfunction impedes anti-tumor immunity in solid cancers but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional co-activator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In …

ObjectivesHeterozygous missense variants in MYBPC1 have been recently identified in 13 patients from 6 families with congenital myopathy with tremor. All the patients had mild skeletal myopathy invariably associated with a distinctive myogenic tremor and hypotonia with gradual clinical improvement. However, no phenotypic description has been reported for the neonatal respiratory impairment that patients may suffer.MethodsWe report 3 new patients from 2 independent families with congenital myopathy with tremor.ResultsTremors and respiratory distress associated with stridor should raise the diagnosis of congenital myopathy with tremors linked to MYBPC1-dominant variants in children with neonatal hypotonia.DiscussionNeonatal severe respiratory impairment requiring intensive noninvasive ventilation because of stridor is described in 2 patients. Stridor was previously reported in one other case and is part …

Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in genome-wide association studies (GWASs). Using childhood body mass index (BMI) as an example, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound. GWAS on each of the estimated phenotypes identified 28 genome-wide significant variants at 13 loci across the 12 estimated phenotypes, one of which was novel (in DAOA) and had not been previously associated with childhood or adult BMI. Genetic studies of changes in human traits over time could uncover novel biological mechanisms influencing quantitative traits.

BackgroundPubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.ResultsLarge-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify …

Background and AimsThe putative association between serum 25-hydroxyvitamin D concentration [25(OH)D] and the risk of cardioembolic stroke (CES) has been examined in observational studies, which indicate controversial findings. We performed Mendelian randomization (MR) analysis to determine the causal relationship of serum 25(OH)D with the risk of CES.Methods and ResultsThe summary statistics dataset on the genetic variants related to 25(OH)D was used from the published GWAS of European descent participants in the UK Biobank, including 417,580 subjects, yielding 143 independent loci in 112 1-Mb regions. GWAS summary data of CES was obtained from GIGASTROKE Consortium, which included European individuals (10,804 cases, 1,234,808 controls).Our results unveiled a causal relationship between 25(OH)D and CES using IVW [OR = 0.82, 95% CI: 0.67-0.98, p = 0.037]. Horizontal …

Bronchopulmonary dysplasia (BPD) is a frequent complication of preterm birth. Despite this, genetic drivers of BPD are poorly understood. The objective of this study is to better understand the impact of if single nucleotide polymorphisms (SNPs) previously associated with BPD by examining associations with other phenotypes. We drew pediatric subjects from the biorepository at the Center for Applied Genomics to identify associations between these SNPs and 2,146 imputed phenotypes. Methylation data, external cohorts, and in silico validation methods were used to corroborate significant associations. We identified 72 SNPs that were previously associated with BPD. We found a significant association between rs3771150 and rs3771171 and mean eosinophil percentage in a European cohort of 6,999 patients and replicated this in external cohorts. Both SNPs were also associated with asthma, COPD and FEV1/FVC ratio. These SNPs displayed associations with methylation probes and were functionally linked to ST2 (IL1RL1) levels in blood. Our findings support a genetic justification for the epidemiological link between BPD and asthma. Given the well-established link between ST2 and type 2 inflammation in asthma, these findings provide a rationale for future studies exploring the role of type 2 inflammation in the pathogenesis of BPD.

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30−0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69−0.88], p = 4.0 × 10−5) or immunosuppressant (n = 354, HR = 0.61 [0 …

BackgroundPrevious studies have implicated both rare copy number variations (CNVs) and common variants in liability for Attention deficit hyperactivity disorder (ADHD). However, how common and rare genetic variants jointly contribute to individual liability requires further investigation in larger cohorts.MethodsThis study is comprised of 9,385 subjects of European decedent and 7,810 subjects of African-American ancestry, who were recruited from the greater Philadelphia area by The Children's Hospital of Philadelphia (CHOP). The polygenic risk score (PRS) of each subject was estimated by the LD-pruning and P-value thresholding (P+ T) methods using PRSice-2. We investigated whether the risk of ADHD follows a polygenic liability threshold model, where 1) the risk of ADHD requires less contribution from common variants in the presence of a rare CNV, and 2) control carriers of ADHD-associated CNV have lower common risk allele burden than noncarriers.ResultsCNVs, previously reported in ADHD cases were significantly associated with ADHD risk in both the European-American cohort and the African-American cohort. Healthy controls subject carrying those same risk CNVs had lower PRSs than healthy controls without risk CNVs in the European-American cohort. This result was further replicated in the African-American cohort. However, PRSs was not significant between case subjects carrying risk CNVs and case subjects without risk CNVs.ConclusionsThese findings provide evidence in support of interactive effects of PRS and ADHD-associated CNVs for disease risk, and add novel insights into the genetic basis of ADHD by …

MethodsTo overcome these challenges, we implemented a tiered testing strategy using multiple sample types to detect both germline and somatic variants. A unique molecular identifier (UMI) ultra-deep targeted gene panel was designed and applied to unconventional samples, such as endothelial cells isolated from lymphatic fluid and cfDNA, to enhance the detection of somatic variants with a low variant allele fraction (< 1%). A total of 358 individuals with complex vascular anomalies were evaluated from our institution’s Complex Lymphatic and Comprehensive Vascular Anomaly Centers. Different genomic analysis techniques, including toutine exome (∼ 80x), high coverage exome (> 400x), ultra-deep coverage targeted sequencing (∼ 100,000 x, panel of 51 genes), and blocker displacement qPCR/Sanger assay were applied to genomic DNA isolated from patient samples from blood, saliva, lesional tissue …

Genome-wide association studies (GWAS) have been instrumental in identifying genetic associations for various diseases and traits. However, uncovering genetic underpinnings among traits beyond univariate phenotype associations remains a challenge. Multi-phenotype associations (MPA), or genetic pleiotropy, offer important insights into shared genes and pathways among traits, enhancing our understanding of genetic architectures of complex diseases. GWAS of biobank-linked electronic health record (EHR) data are increasingly being utilized to identify MPA among various traits and diseases. However, methodologies that can efficiently take advantage of distributed EHR to detect MPA are still lacking. Here, we introduce mixWAS, a novel algorithm that efficiently and losslessly integrates multiple EHRs via summary statistics, allowing the detection of MPA among mixed phenotypes while accounting for …

Dyslipidemia, as a metabolic risk factor, with the strongest and most heritable independent cause of cardiovascular diseases worldwide. We investigated the familial transmission patterns of dyslipidemia through a longitudinal family-based cohort, the Tehran Cardiometabolic Genetic Study (TCGS) in Iran. We enrolled 18,729 individuals (45% were males) aged > 18 years (mean: 38.15 (15.82)) and observed them over five 3-year follow-up periods. We evaluated the serum concentrations of total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol with the first measurement among longitudinal measures and the average measurements (AM) of the five periods. Heritability analysis was conducted using a mixed-effect framework with likelihood-based and Bayesian approaches. The periodic prevalence and heritability of dyslipidemia were estimated to be 65.7 and 42 …

Methods for diagnosing and treating conduct disorder are encompassed, wherein diagnosis and treatment may be based upon an assessment of genetic alterations in metabotropic glutamate receptor (mGluR) network genes and wherein treatment is with nonspecific activators of mGluRs such as fasoracetam.

Voriconazole exposure is associated with skin cancer, but it is unknown how the full spectrum of its metabolizer phenotypes impacts this association. We conducted a retrospective cohort study to determine how variation in metabolism of voriconazole as measured by metabolizer status of CYP2C19 is associated with the total number of skin cancers a patient develops and the rate of development of the first skin cancer after treatment. There were 1,739 organ transplant recipients with data on CYP2C19 phenotype. Of these, 134 were exposed to voriconazole. There was a significant difference in the number of skin cancers after transplant based on exposure to voriconazole, metabolizer phenotype, and the interaction of these two (p< 0.01 for all three). This increase was driven primarily by number of squamous cell carcinomas among rapid metabolizes with voriconazole exposure (p< 0.01 for both). Patients exposed to voriconazole developed skin cancers more rapidly than those without exposure (Fine-Grey hazard ratio 1.78, 95% confidence interval 1.19–2.66). This association was similarly driven by development of SCC (Fine-Grey hazard ratio 1.83, 95% confidence interval 1.14–2.94). Differences in voriconazoles metabolism are associated with an increase in the number of skin cancers developed after transplant, particularly SCC.

The differential performance of polygenic risk scores (PRSs) by group is one of the major ethical barriers to their clinical use. It is also one of the main practical challenges for any implementation effort. The social repercussions of how people are grouped in PRS research must be considered in communications with research participants, including return of results. Here, we outline the decisions faced and choices made by a large multi-site clinical implementation study returning PRSs to diverse participants in handling this issue of differential performance. Our approach to managing the complexities associated with the differential performance of PRSs serves as a case study that can help future implementers of PRSs to plot an anticipatory course in response to this issue.

Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of cellular heterogeneity and the dynamics of gene expression, bearing profound significance in stem cell research. Depending on the starting materials used for analysis, scRNA-seq encompasses scRNA-seq and single-nucleus RNA sequencing (snRNA-seq). scRNA-seq excels in capturing cellular heterogeneity and characterizing rare cell populations within complex tissues, while snRNA-seq is advantageous in situations where intact cell dissociation is challenging or undesirable (eg, epigenomic studies). A number of scRNA-seq technologies have been developed as of late, including but not limited to droplet-based, plate-based, hydrogel-based, and spatial transcriptomics. The number of cells, sequencing depth, and sequencing length in scRNA-seq can vary across different studies. Addressing current technical challenges …

BackgroundCLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID).ObjectivesThis study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID.MethodsThe investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array.ResultsThis study showed …

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with …

Background Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology.Methods Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene.Results We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP …

BackgroundPatients with birth defects (BD) exhibit an elevated risk of cancer. We aimed to investigate the potential link between pediatric cancers and BDs, exploring the hypothesis of shared genetic defects contributing to the coexistence of these conditions.MethodsThis study included 1454 probands with BDs (704 females and 750 males), including 619 (42.3%) with and 845 (57.7%) without co-occurrence of pediatric onset cancers. Whole genome sequencing (WGS) was done at 30X coverage through the Kids First/Gabriella Miller X01 Program.Results8211 CNV loci were called from the 1454 unrelated individuals. 191 CNV loci classified as pathogenic/likely pathogenic (P/LP) were identified in 309 (21.3%) patients, with 124 (40.1%) of these patients having pediatric onset cancers. The most common group of CNVs are pathogenic deletions covering the region ChrX:52,863,011-55,652,521, seen in 162 …

BackgroundAutoantibody-mediated cytopenias (AICs) regularly occur in profoundly IgG-deficient common variable immunodeficiency (CVID) patients. The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear.ObjectiveTo determine reactivity, clonality and provenance of AIC-associated IgM autoantibodies in CVID patients.MethodsWe utilized glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan binding profiles were used to identify auto-reactive clones across B cell subsets, specifically circulating marginal zone-like (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes and responses of tonsillar MZ B cells to different T helper cell subsets were determined by confocal microscopy, RNA-sequencing, and co-cultures, respectively.ResultsAutoreactive IgM coated erythrocytes and platelets from many CVID …

Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, known vascular anomaly of Turner syndrome. However, previous studies have described other vascular malformations as a rare feature of Turner syndrome and suggested that vascular abnormalities in individuals with Turner syndrome may be more generalized. In this study, we describe two individuals with co‐occurrence of Turner syndrome and vascular malformations with a lymphatic component. In these individuals, genetic testing of the lesional tissue revealed a somatic pathogenic variant in PIK3CA—a known and common cause of lymphatic …

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild …

Background The genetic architecture of juvenile idiopathic arthritis (JIA) remains only partially comprehended. There is a clear imperative for continued endeavors to uncover insights into the underlying causes of JIA. Methods This study encompassed a comprehensive spectrum of endeavors, including conducting a JIA GWAS meta-analysis that incorporated data from 4,550 JIA cases and 18 446 controls. We employed in silico and genome-editing approaches to prioritize target genes. To investigate pleiotropic effects, we conducted phenome-wide association studies. Cell-type enrichment analyses were performed by integrating bulk and single-cell sequencing data. Finally, we delved into potential druggable targets for JIA. Results Fourteen genome-wide significant non-HLA loci were identified including four novel loci, each exhibiting pleiotropic …

Owing to the inefficacy of available treatments, the survival rate of patients with metastatic prostate cancer (mPCa) is severely decreased. Therefore, it is crucial to identify new therapeutic targets to increase the survival of mPCa patients. This study aim was to identify the most relevant regulators of mPCa onset by performing two high-throughput CRISPR/Cas9 screenings. Furthermore, some of the top hits were validated using small interfering RNA (siRNA) technology, with protein arginine methyltransferase 7 (PRMT7) being the best candidate. Its inhibition or depletion via CRISPR significantly reduced mPCa cell capacities in vitro. Furthermore, PRMT7 ablation reduced mPCa appearance in chicken chorioallantoic membrane and mouse xenograft assays. Molecularly, PRMT7 reprograms the expression of several adhesion molecules through methylation of several transcription factors, such as FoxK1 or NR1H2, which results in primary tumor PCa cell adhesion loss and motility gain. Moreover, PRMT7 is upregulated in advanced stages of Spanish PCa tumor samples and PRMT7 pharmacological inhibition reduces the dissemination of mPCa cells. Thus, here is shown that PRMT7 is a potential therapeutic target and biomarker of mPCa.

BackgroundTesticular germ cell tumor (TGCT) is the most common cancer among young White men. TGCT is highly heritable, although there are no known high-penetrance predisposition genes. CHEK2 is associated with moderate TGCT risk.ObjectiveTo identify coding genomic variants associated with predisposition to TGCT.Design, setting, and participantsThe study involved 293 men with familial or bilateral (high risk; HR)-TGCT representing 228 unique families and 3157 cancer-free controls.Outcome measurements and statistical analysisWe carried out exome sequencing and gene burden analysis to identify associations with TGCT risk.Results and limitationsGene burden association identified several genes, including loss-of-function variants of NIN and QRSL1. We identified no statistically significant association with the sex- and germ-cell development pathways (hypergeometric overlap test: p = 0.65 for …

The co-occurrence and familial clustering of neurodevelopmental disorders and immune disorders suggest shared genetic risk factors. Based on genome-wide association summary statistics from five neurodevelopmental disorders and four immune disorders, we conducted genome-wide, local genetic correlation and polygenic overlap analysis. We further performed a cross-trait GWAS meta-analysis. Pleotropic loci shared between the two categories of diseases were mapped to candidate genes using multiple algorithms and approaches. Significant genetic correlations were observed between neurodevelopmental disorders and immune disorders, including both positive and negative correlations. Neurodevelopmental disorders exhibited higher polygenicity compared to immune disorders. Around 50%-90% of genetic variants of the immune disorders were shared with neurodevelopmental disorders. The cross …

Background Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic germline variants in patients without a family history remains unclear. Methods Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene pathogenic or likely pathogenic variants in patients was compared with 2 cancer-free control cohorts. Matched tumor DNA sequencing was evaluated for second hits, and germline DNA array data from 5585 neuroblastoma patients and 23 505 cancer-free control children were analyzed to identify rare germline copy number variants. Patients with germline pathogenic or likely pathogenic variants were compared with those without to test for association with clinical characteristics, tumor features, and survival …

The advent of long-read single-cell transcriptome sequencing (lr-scRNA-Seq) represents a significant leap forward in single-cell genomics. With the recent introduction of R10 flowcells by Oxford Nanopore, we propose that previous computational methods designed to handle high sequencing error rates are no longer relevant, and that the prevailing approach using short reads to compile "barcode space" (candidate barcode list) to de-multiplex long reads are no longer necessary. Instead, computational methods should now shift focus on harnessing the unique benefits of long reads to analyze transcriptome complexity. In this context, we introduce a comprehensive suite of computational methods named Single-Cell Omics for Transcriptome CHaracterization (SCOTCH). Our method is compatible with the single-cell library preparation platform from both 10X Genomics and Parse Biosciences, facilitating the analysis of special cell populations, such as neurons, hepatocytes and developing cardiomyocytes. We specifically re-formulated the transcript mapping problem with a compatibility matrix and addressed the multiple-mapping issue using probabilistic inference, which allows the discovery of novel isoforms as well as the detection of differential isoform usage between cell populations. We evaluated SCOTCH through analysis of real data across different combinations of single-cell libraries and sequencing technologies (10X + Illumina, Parse + Illumina, 10X + Nanopore_R9, 10X + Nanopore_R10, Parse + Nanopore_R10), and showed its ability to infer novel biological insights on cell type-specific isoform expression. These datasets enhance the …

Glioblastoma (GBM) is an aggressive brain cancer with a median survival time of 14.6 months after diagnosis. GBM cells have altered metabolism and exhibit the Warburg effect, preferentially producing lactate under aerobic conditions. After standard-of-care treatment for GBM, there is an almost 100% recurrence rate. Hypoxia-adapted, treatment-resistant GBM stem-like cells are thought to drive this high recurrence rate. We used human T98G GBM cells as a model to identify differential gene expression induced by hypoxia and to search for potential therapeutic targets of hypoxia adapted GBM cells. RNA sequencing (RNAseq) and bioinformatics were used to identify differentially expressed genes (DEGs) and cellular pathways affected by hypoxia. We also examined expression of lactate dehydrogenase (LDH) genes using qRT-PCR and zymography as LDH dysregulation is a feature of many cancers. We found 2630 DEGs significantly altered by hypoxia (p < 0.05), 1241 upregulated in hypoxia and 1389 upregulated in normoxia. Hypoxia DEGs were highest in pathways related to glycolysis, hypoxia response, cell adhesion and notably the endoplasmic reticulum, including the inositol-requiring enzyme 1 (IRE1)-mediated unfolded protein response (UPR). These results, paired with numerous published preclinical data, provide additional evidence that inhibition of the IRE1-mediated UPR may have therapeutic potential in treating GBM. We propose a possible drug repurposing strategy to simultaneously target IRE1 and the spleen tyrosine kinase (SYK) in patients with GBM.

Joubert syndrome (JBTS) is a Mendelian disorder of the primary cilium defined by the clinical triad of hypotonia, developmental delay, and a distinct cerebellar malformation called the molar tooth sign. JBTS is inherited in an autosomal recessive, autosomal dominant, or X‐linked recessive manner. Though over 40 genes have been identified as causal for JBTS, molecular diagnosis is not made in 30%–40% of individuals who meet clinical criteria. TOPORS encodes topoisomerase I‐binding arginine/serine‐rich protein, and homozygosity for a TOPORS missense variant (c.29C > A; p.(Pro10Gln)) was identified in individuals with the ciliopathy oral‐facial‐digital syndrome in two families of Dominican descent. Here, we report an additional proband of Dominican ancestry with JBTS found by exome sequencing to be homozygous for the identical p.(Pro10Gln) TOPORS missense variant. Query of the Mount Sinai Bio …

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is undefined. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGS WBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio= 0.55 per standard deviation increase in PGS WBC [95% CI, 0.30–0.94], p= 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n= 1,724, hazard ratio [HR]= 0.78 [0.69–0.88], p= 4.0× 10− 5) or immunosuppressant (n= 354, HR= 0.61 [0.38–0.99], p= 0.04). A …

Hypertension is a global problem that affects more than 1 billion people worldwide with the increased prevalence year by year [1, 2]. It contributes to major impacts on health including morbidity and all-cause mortality, as well as consumption of substantial health care expenses. Understanding the complex pathophysiology and risk factors involved in the development of elevated blood pressure can help treat the disease to better prevent life-threatening conditions and alleviate the socio-economic burden. The hereditary nature of hypertension relies on that up to 30% of blood pressure variation is due to genetics and an individual's genetic predisposition to hypertensive disease ranges from 15% to 35%[3]. So far, 87 rare single-nucleotide variants and more than 1477 common single-nucleotide polymorphisms have been discovered to be associated with blood pressure traits [4, 5]. It is now generally believed that …

Background & AimsUlcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.MethodsHLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.ResultsThese studies identified HLA-DPA1∗01:03-DPB1∗04 …

A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in …

Method:The summary statistics dataset related to serum MUFAs was used from the published GWAS of European descent in UK Biobank participants (N= 114,999). Genetic variants underlying angina, atherosclerotic, IHD, MI, and BP events were ascertained using a GWAS dataset of 461,880 (case= 14,828, control= 447,052), 463,010 (case= 12,171, control= 450,839), 361,194 (case= 20,857, control= 340,337), 462,933 (case= 10,616, control= 452,317), and 461,880 (case= 124,227, control= 337,653) European descent participants from the UK Biobank, respectively.Results:Our results show that MUFAs were associated with angina [OR IVW= 1.005, 95% CI: 1.003–1.007, p=< 0.001; Cochran's Q= 23.89, p= 0.717, I 2= 0.0%; Egger intercept=-0.0003, p= 0.289], atherosclerotic [OR IVW= 1.005, 95% CI: 1.003–1.007, p=< 0.001; Cochran's Q= 42.71, p= 0.078, I 2= 27.4%; Egger intercept=-0.0004, p= 0.146], IHD [OR IVW= 1.004, 95% CI: 1.001–1.007, p= 0.005; Cochran's Q= 42.75, p= 0.172, I 2= 18.1%; Egger intercept=-0.0001, p= 0.827], MI [OR IVW= 1.001, 95% CI: 0.999–1.003, p= 0.199; Cochran's Q= 23.03, p= 0.631, I 2= 0.0%; Egger intercept=-0.0003, p= 0.196], and BP [OR WM= 1.008, 95% CI: 1.001–1.015, p= 0.022; Cochran's Q= 52.87, p= 0.015, I 2= 37.6%; Egger intercept= 0.0002, p= 0.779]. These results remained consistent using different MR method and sensitivity analyses.Conclusion:These findings prompt significant questions about the function of MUFAs in the progression of CVD events. Further research is required to elucidate the connections between MUFAs and CVD to contribute to health policy decisions in reducing CVD risk.

Introduction: Postural orthostatic tachycardia syndrome (POTS) is more common in Caucasian individuals with a positive family history, while the risk in females is ~4-times of that in males. To date, the etiology of POTS is poorly understood. Hypothesis: Integrative sequencing and translational approaches to identify its genetic underpinning may better understand its pathogenesis and molecular mechanisms for the development of novel precision-based therapies. Methods: We adopted exome sequencing to evaluate the etiology and molecular mechanisms of POTS. We examined a unique collection of 87 unrelated pediatric POTS cases (61 females and 26 males, 6~21 years old), using exome sequencing. Non-relationship between individuals were validated by genome wide genotyping and identity by descent (IBD) analysis. Results: All the individuals were classified as European by principal component analysis …

GATA-binding factor 1 (GATA1) is a transcription factor that governs the development and function of multiple hematopoietic cell lineages. GATA1 is expressed in hematopoietic stem and progenitor cells (HSPCs) and is essential for erythroid lineage commitment; however, whether it plays a role in hematopoietic stem cell (HSC) biology and the development of myeloid cells, and what that role might be, remains unclear. We initially set out to test the role of eosinophils in experimental autoimmune encephalomyelitis (EAE), a model of central nervous system autoimmunity, using mice lacking a double GATA-site (ΔdblGATA), which lacks eosinophils due to the deletion of the dblGATA enhancer to Gata1, which alters its expression. ΔdblGATA mice were resistant to EAE, but not because of a lack of eosinophils, suggesting that these mice have an additional defect. ΔdblGATA mice with EAE had fewer inflammatory …

BackgroundAmbient air pollution exposure increases the incidence and severity of pediatric asthma. Despite this, we lack effective therapies to protect patients from the impact of ambient air pollution exposure. A roadblock is the inability to identify patients that are affected by air pollution.ObjectiveTo examine the association between AAP sensitivity determined by individual exposure prior to asthma exacerbations and the severity of asthma in pediatric patients.MethodsWe assess the association between spikes in ambient air pollution and asthma exacerbations. Patients were considered sensitive to a specific pollutant if they experienced an asthma exacerbation immediately following a spike in the concentration of that pollutant. Cut off values for these spikes were determined as two standard deviations above the mean concentration two weeks prior and two weeks post the days leading up to an asthma …

2023-04-27 Assigned to THE CHILDREN'S HOSPITAL OF PHILADELPHIA reassignment THE CHILDREN'S HOSPITAL OF PHILADELPHIA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ELIA, JOSEPHINE, GLESSNER, JOSEPH, HAKONARSON, HAKON

Insights Image for "Treatment of severe Kaposiform Lymphangiomatosis positive for NRAS mutation by MEK-inhibition" Insights Image for "Treatment of severe Kaposiform Lymphangiomatosis positive for NRAS mutation by MEK-inhibition" Pediatr Res. 2023 Dec;94(6):2117. doi: 10.1038/s41390-023-02755-3. Epub 2023 Aug 7. Authors Guy Chowers # 1 , Gadi Abebe-Campino # 2 3 , Hana Golan # 2 3 , Asaf Vivante 1 2 4 , Shoshana Greenberger 2 5 , Michalle Soudack 6 , Galia Barkai 2 7 , Ilana Fox-Fisher 8 , Dong Li 9 , Michael March 9 , Mark R Battig 9 , Hakon Hakonarson 9 10 11 , Denise Adams 12 , Yoav Dori 10 13 , Adi Dagan 14 15 16 Affiliations 1 Pediatrics B, Edmond and Lili Safra Children's Hospital, Chaim Sheba Medical Center at Tel Hashomer, Ramat-Gan, Israel. 2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 3 Pediatric Hematology Oncology division, Edmond and Lily Safra …

Hallux valgus is a common form of foot deformity, and genetic factors contribute substantially to the pathogenesis of hallux valgus deformity. We conducted a genetic study on the structural variants underlying familial hallux valgus using whole exome sequencing approach. Twenty individuals from five hallux valgus families and two sporadic cases were included in this study. A total of 372 copy number variations were found and passed quality control filtering. Among them, 43 were only present in cases but not in controls or healthy individuals in the database of genomic variants. The genes covered by these copy number variations were enriched in gene sets related to immune signaling pathway, and cytochrome P450 metabolism. The hereditary CNVs demonstrate a dominant inheritance pattern. Two candidate pathogenic CNVs were further validated by quantitative-PCR. This study suggests that hallux valgus is a degenerative joint disease involving the dysregulation of immune and metabolism signaling pathways.

PurposeThe aim of this study was to assess the performance of cell-free DNA (cfDNA) screening to detect sex chromosome aneuploidies (SCAs) in an unselected obstetrical population with genetic confirmation.MethodsThis was a planned secondary analysis of the multicenter, prospective SNP-based Microdeletion and Aneuploidy RegisTry (SMART) study. Patients receiving cfDNA results for autosomal aneuploidies and who had confirmatory genetic results for the relevant sex chromosomal aneuploidies were included. Screening performance for SCAs, including monosomy X (MX) and the sex chromosome trisomies (SCT: 47,XXX; 47,XXY; 47,XYY) was determined. Fetal sex concordance between cfDNA and genetic screening was also evaluated in euploid pregnancies.ResultsA total of 17,538 cases met inclusion criteria. Performance of cfDNA for MX, SCTs, and fetal sex was determined in 17,297, 10,333, and …

We report a 20-year-old, female, adopted Indian patient with over 662 Mb regions of homozy-gosity who presented with intellectual disability, ataxia, schizophrenia, retinal dystrophy, moder-ate-to-severe progressive sensorineural hearing loss (SNHL), congenital hypothyroidism, cleft mi-tral valve with mild mitral valve regurgitation, and dysmorphic features. Exome analysis first on a clinical basis and subsequently on research reanalysis uncovered pathogenic variants in three nu-clear genes following two modes of inheritance that were causal to her complex phenotype. These included (1) compound heterozygous variants in BBS6 potentially causative for Bardet–Biedl syn-drome 6; (2) a homozygous, known pathogenic variant in the stereocilin (STRC) gene associated with nonsyndromic deafness; and (3) a homozygous variant in dual oxidase 2 (DUOX2) gene asso-ciated with congenital hypothyroidism. A variant of uncertain significance was identified in a fourth gene, troponin T2 (TNNT2), associated with cardiomyopathy but not the cleft mitral valve, with mild mitral regurgitation seen in this case. This patient was the product of an apparent first-degree relationship, explaining the multiple independent inherited findings. This case high-lights the need to carefully evaluate multiple independent genetic etiologies for complex pheno-types, particularly in the case of consanguinity, rather than presuming unexplained features are expansions of known gene disorders.

PurposeAssessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.MethodsTo enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores (PRS), monogenic risks, family history, and clinical risk assessments via a Genome Informed Risk Assessment (GIRA) report and will assess uptake of care recommendations after return of results.ResultsGIRAs include summary care recommendations for 11 conditions, education pages, and …

Compositions and methods for the detection and treatment of obesity and other neurological disorders are provided.

This application relates to methods of diagnosing and treating anorexia nervosa (AN) and binge eating disorder (BED) with a nonselective activator of metabotropic glutamate receptors (mGluRs).

As large-scale genomic screening becomes increasingly prevalent, understanding the influence of actionable results on healthcare utilization is key to estimating the potential long-term clinical impact. The eMERGE network sequenced individuals for actionable genes in multiple genetic conditions and returned results to individuals, providers, and the electronic health record. Differences in recommended health services (laboratory, imaging, and procedural testing) delivered within 12 months of return were compared among individuals with pathogenic or likely pathogenic (P/LP) findings to matched individuals with negative findings before and after return of results. Of 16,218 adults, 477 unselected individuals were found to have a monogenic risk for arrhythmia (n = 95), breast cancer (n = 96), cardiomyopathy (n = 95), colorectal cancer (n = 105), or familial hypercholesterolemia (n = 86). Individuals with P/LP results …

The power of genetic diversity in genome-wide association studies of lipids (vol 600, pg 675, 2021) | Scholarly Publications Skip to main content Universiteit Leiden Leiden University Scholarly Publications Home Submit About Select Collection Search box Graham, SE; Clarke, SL; Wu, KHH; Kanoni, S.; Zajac, GJM; Ramdas, S.; ... ; Stark, K. (2023) The power of genetic diversity in genome-wide association studies of lipids (vol 600, pg 675, 2021) Article / Letter to editor All authors Graham, SE; Clarke, SL; Wu, KHH; Kanoni, S.; Zajac, GJM; Ramdas, S.; Surakka, I.; Ntalla, I.; Vedantam, S.; Winkler, TW; Locke, AE; Marouli, E.; Hwang, MY; Han, S.; Narita, A.; Choudhury, A.; Bentley, AR; Ekoru, K.; Verma, A.; Trivedi, B.; Martin, HC; Hunt, KA; Hui, Q.; Klarin, D.; Zhu, X.; Thorleifsson, G.; Helgadottir, A.; Gudbjartsson, DF; Holm, H.; Olafsson, I.; Akiyama, M.; Sakaue, S.; Terao, C.; Kanai, M.; Zhou, W.; Brumpton, BM; Rasheed, H.; …

Bartter syndrome (BS) manifests as hypokalemic and hypochloremic metabolic alkalosis and hyperreninemic hyperaldosteronism. Loss-of-function (LoF) mutations in seven genes are known to cause different subtypes of BS. We sought the genetic cause of BS in a 17-year-old patient who presented with progressive nephrocalcinosis, hypercalciuria, polyuria, metabolic alkalosis, hypokalemia, significantly high urine chloride, failure-to-thrive, hypergammaglobulinemia, abnormal cerebral white matter signal changes, autoinflammation, and moderate intellectual disability. No mutations were identified in previously BS-associated genes in this patient with consanguineous parents, and all seven genes resided outside of genomic regions of homozygosity (ROH). Instead, whole-exome sequencing and homozygosity mapping identified a homozygous intronic mutation, c. 2702-2A> G, in the epidermal growth factor …

BACKGROUND As a collaboration model between the International HundredK+ Cohorts Consortium (IHCC) and the Davos Alzheimer's Collaborative (DAC), our aim was to develop a trans‐ethnic genomic informed risk assessment (GIRA) algorithm for Alzheimer's disease (AD). METHODS The GIRA model was created to include polygenic risk score calculated from the AD genome‐wide association study loci, the apolipoprotein E haplotypes, and non‐genetic covariates including age, sex, and the first three principal components of population substructure. RESULTS We validated the performance of the GIRA model in different populations. The proteomic study in the participant sites identified proteins related to female infertility and autoimmune thyroiditis and associated with the risk scores of AD. CONCLUSIONS As the initial effort by the IHCC to leverage existing large‐scale datasets in a collaborative setting …

(Cell Reports 34, 108917; March 30, 2021) After the publication of this paper, which was originally published with the March 30, 2021 issue of Cell Reports, the authors discovered that contributor Kanika Jain, who performed immunohistochemistry used in the paper, was omitted from the author list. Jain should have been designated as the eighth author, after Li Zhai and before Zahidul Alam. During the time that the research was being conducted and the manuscript being written, Jain was affiliated with the Department of Pathology and Laboratory Medicine at Children's Hospital of Philadelphia, PA, USA. All authors have approved this post-publication acknowledgement of Jain's authorship. They apologize for the error and any confusion it may have caused.

ObjectiveAccumulative evidence indicates a critical role of mitochondrial function in autism spectrum disorders (ASD), implying that ASD risk may be linked to mitochondrial dysfunction due to DNA (mtDNA) variations. Although a few studies have explored the association between mtDNA variations and ASD, the role of mtDNA in ASD is still unclear. Here, we aimed to investigate whether mitochondrial DNA haplogroups are associated with the risk of ASD.MethodTwo European cohorts and an Ashkenazi Jewish (AJ) cohort were analyzed, including 2,062 ASD patients in comparison with 4,632 healthy controls. DNA samples were genotyped using Illumina HumanHap550/610 and Illumina 1M arrays, inclusive of mitochondrial markers. Mitochondrial DNA (mtDNA) haplogroups were identified from genotyping data using HaploGrep2. A mitochondrial genome imputation pipeline was established to detect mtDNA …

BAG3 is a 575 amino acid protein that is found throughout the animal kingdom and homologs have been identified in plants. The protein is expressed ubiquitously but is most prominent in cardiac muscle, skeletal muscle, the brain and in many cancers. We describe BAG3 as a quintessential multi-functional protein. It supports autophagy of both misfolded proteins and damaged organelles, inhibits apoptosis, maintains the homeostasis of the mitochondria, and facilitates excitation contraction coupling through the L-type calcium channel and the beta-adrenergic receptor. High levels of BAG3 are associated with insensitivity to chemotherapy in malignant cells whereas both loss of function and gain of function variants are associated with cardiomyopathy.

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found …

BackgroundAlthough food allergies are considered common, relatively little is known about disparities in food allergy by race in the United States.ObjectiveTo evaluate differences in reported food allergy and food-associated anaphylaxis among individuals enrolled in a longitudinal cohort study from metropolitan Detroit, Michigan.MethodsParticipants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) were asked about food allergies, including the inciting food and associated symptoms. Individuals were considered to have food-associated anaphylaxis if symptoms coincided with established clinical criteria. Logistic regression was used to assess whether race difference persisted after adjusting for and stratifying by potential confounders. African genetic ancestry was individually estimated among African American SAPPHIRE participants to assess whether …

This disclosure provides new genetic targets, diagnostic methods, and therapeutic treatment regimens for multiple autoimmune disorders, including pediatric autoimmune disorders that are co-inherited and genetically shared. The disclosure, for example, provides methods of diagnosing or determining a susceptibility for one or more autoimmune diseases and methods of determining treatment protocols for patients with one or more autoimmune diseases based on determining if the patients have genetic alterations in particular genes.

In accordance with the present invention, a method for detecting a propensity for developing schizophrenia in a patient in need thereof is provided. An exemplary method entails detecting the presence of at least one CNV containing nucleic acid in a target polynucleotide wherein if said CNV is present, said patient has an increased risk for developing schizophrenia, wherein said CNV containing nucleic acid is selected from the group of CNVs that are either exclusive to, or significantly overrepresented in schizophrenia. See Tables 2 and 3). In another embodiment of the invention, a method for identifying agents which alter neuronal signaling and/or morphology is provided. Such a method comprises providing cells expressing at least one of the CNVs listed above (step a); providing cells which express the cognate wild type sequences corresponding to the CNV (step b); contacting the cells from each sample with a …

2023-04-27 Assigned to THE CHILDREN'S HOSPITAL OF PHILADELPHIA reassignment THE CHILDREN'S HOSPITAL OF PHILADELPHIA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ALMOGUERA, Berta, SLEIMAN, Patrick, VAZQUEZ, Lyam, HAKONARSON, HAKON

Dear Editor: Central nervous system tumors in the brain or spine are the most common solid tumors in children, which accounts for about 25% of cancers in children younger than 15 years of age, and are the most common cause of cancer deaths in children [1]. The 5-year survival rate for central nervous system neoplasms has increased dramatically to 74% for patients under 18 years old (97% for benign/borderline malignant tumors) in 2022, compared to 20% in the 1970s [1]. Without cure treatments and specific medications for many brain cancers, the dramatic increase of survival rate is largely due to improved hospital care and availability of clinical resources. The length of hospitalization of pediatric patients with brain cancer is an important indicator of prognosis as it reflects the required medical effort needed to care for these patients. The length of hospitalization is also critical for the healthcare system as …

BackgroundNeurodevelopmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are examples of complex and partially overlapping phenotypes that often lack definitive corroborating genetic information. ADHD and ASD have complex genetic associations implicated by rare recurrent copy number variations (CNVs). Both of these NDDs have been shown to share similar biological etiologies as well as genetic pleiotropy.MethodsPlatforms aimed at investigating genetic-based associations, such as high-density microarray technologies, have been groundbreaking techniques in the field of complex diseases, aimed at elucidating the underlying disease biology. Previous studies have uncovered CNVs associated with genes within shared candidate genomic networks, including glutamate receptor genes, across multiple different NDDs. To examine shared …

This disclosure relates to the identification of a subset of mGluR network gene CNVs that are predictive of efficacy of treatment with fasoracetam, as well as the identification of an mGluR network gene CNV that is predictive of an increased likelihood of having ADHD as well as having certain symptoms associated with ADHD.

Polygenic risk scores (PRS) have potential to improve healthcare by identifying individuals at elevated risk for common complex conditions. Use of PRS in clinical practice, however, requires careful assessment of the needs and capabilities of patients, providers, and healthcare systems. The electronic Medical Records and Genomics (eMERGE) Network is conducting a collaborative study which will return PRS to 25,000 pediatric and adult participants. All participants will receive a risk report, potentially classifying them as high risk (∼2-10% per condition) for one or more of 10 conditions based on PRS. The study population is enriched by participants from racial and ethnic minority populations, underserved populations, and populations who experience poorer medical outcomes.All ten eMERGE clinical sites conducted focus groups, interviews, and/or surveys to understand educational needs among key …

BackgroundKaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy.MethodsThe NRAS somatic mutation was …

Objective One goal of prenatal genetic screening is to optimize perinatal care and improve infant outcomes. We sought to determine whether high‐risk cfDNA screening for 22q11.2 deletion syndrome (22q11.2DS) affected prenatal or neonatal management. Methods This was a secondary analysis from the SMART study. Patients with high‐risk cfDNA results for 22q11.2DS were compared with the low‐risk cohort for pregnancy characteristics and obstetrical management. To assess differences in neonatal care, we compared high‐risk neonates without prenatal genetic confirmation with a 1:1 matched low‐risk cohort. Results Of 18,020 eligible participants enrolled between 2015 and 2019, 38 (0.21%) were high‐risk and 17,982 (99.79%) were low‐risk for 22q11.2DS by cfDNA screening. High‐risk participants had more prenatal diagnostic testing (55.3%; 21/38 vs. 2.0%; 352/17,982, p < 0.001) and fetal …

The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed seven associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase …

BackgroundGenomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility.MethodsWe examined the prevalence of GDs among participants in the Chronic Kidney Disease in Children (CKiD) cohort II (n= 248), Chronic Renal Insufficiency Cohort (CRIC) study (n= 3375), Columbia University CKD Biobank (CU-CKD; n= 1986), and the Family Investigation of Nephropathy and Diabetes (FIND; n= 1318) compared with 30,746 controls. We also performed a phenome-wide association analysis (PheWAS) of GDs in the electronic MEdical Records and GEnomics (eMERGE; n= 11,146) cohort.ResultsWe found nine out of 248 (3.6%) CKiD II participants carried a GD, replicating prior findings in pediatric CKD. We also identified GDs in 72 out of 6679 (1.1%) adult patients with CKD in the CRIC, CU-CKD, and FIND cohorts, compared with 199 out of 30,746 (0 …

Children with birth defects (BD) express distinct clinical features that often have various medical consequences, one of which is predisposition to the development of cancers. Identification of the underlying genetic mechanisms related to the development of cancer in BD patients would allow for preventive measures. We performed a whole genome sequencing (WGS) study on blood-derived DNA samples from 1566 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumors, 767 cancer-free BD probands, and 345 healthy individuals. Exclusive recurrent variants were identified in BD-cancer and BD-only patients and mapped to their corresponding genomic regions. We observed statistically significant overlaps for protein-coding/ncRNA with exclusive variants in exons, introns, ncRNAs, and 3’UTR regions. Exclusive exonic variants, especially synonymous …

AMOTL1 encodes angiomotin‐like protein 1, an actin‐binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157–161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi‐organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157–161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in …

The mechanisms by which FOXP3+ T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe or vaccine recognition and away from self-reactivity remain incompletely understood. To explore underappreciated heterogeneity in human Tfr cell development, function, and localization, we used paired TCRVA/TCRVB sequencing to distinguish tonsillar Tfr cells that are clonally related to natural regulatory T cells (nTfr) from those likely induced from T follicular helper (Tfh) cells (iTfr). The proteins iTfr and nTfr cells differentially expressed were used to pinpoint their in situ locations via multiplex microscopy and establish their divergent functional roles. In silico analyses and in vitro tonsil organoid tracking models corroborated the existence of separate Treg-to-nTfr and Tfh-to-iTfr developmental trajectories. Our results identify human iTfr cells as a distinct CD38+, germinal center–resident, Tfh …

Clostridioides difficile (C. diff.) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. diff. do not develop any infection while others develop severe or recurrent infections. To identify common genetic variants associated with CDI, we performed a genome-wide association analysis in 19,861 participants (1349 cases; 18,512 controls) from the Electronic Medical Records and Genomics (eMERGE) Network. Using logistic regression, we found strong evidence for genetic variation in the DRB locus of the MHC (HLA) II region that predisposes individuals to CDI (P > 1.0 × 10–14; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring …

Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in~ 800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a~ 11 and~ 14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of~ 220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic …

A complex COL6A3 mutation identification: it takes an international village - Archive ouverte HAL Accéder directement au contenu Documentation FR Français (FR) Anglais (EN) Se connecter HAL science ouverte Recherche Loading... Recherche avancée Information de documents Titres Titres Sous-titre Titre de l'ouvrage Titre du volume (Série) Champ de recherche par défaut (multicritères) + texte intégral des PDF Résumé Texte intégral indexé des documents PDF Mots-clés Type de document Sous-type de document Tous les identifiants du document Identifiant HAL du dépôt Langue du document (texte) Pays (Texte) Ville À paraître (true ou false) Ajouter Auteur Auteur (multicritères) Auteur (multicritères) Auteur : Nom complet Auteur : Nom de famille Auteur : Prénom Auteur : Complément de nom, deuxième prénom Auteur : Organisme payeur Auteur : IdHal (chaîne de caractères) Auteur : Fonction Auteur : personID …

Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p. Gly12Asp and p. Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar …

Circassians and Chechens in Jordan, both with Caucasian ancestry, are genetically isolated due to high rate of endogamous marriages. Recent interest in these populations has led to studies on their genetic similarities, differences, and epidemiological differences in various diseases. Research has explored their predisposition to conditions like diabetes, hypertension, and cancer. Moreover, pharmacogenetic (PGx) studies have also investigated medication response variations within these populations, and forensic studies have further contributed to understanding these populations. In this review article, we first discuss the background of these minority groups. We then show the results of a principle component analysis (PCA) to investigate the genetic relationships between Circassian and Chechen populations living in Jordan. We here present a summary of the findings from the 10 years of research conducted on …

In the version of this article originally published, the surname of author Stefan Johansson was misspelled as Johanson. In the abstract and “Genome-wide association analyses” section of the Results, the number of loci associated with preterm birth was shown as six instead of seven. In addition, there was a production error in the Figure 1a y-axis units shown below 0, where “10” and “20” were shown as negative numbers. The errors have been corrected in the HTML and PDF versions of the article.

BackgroundAsthma is a chronic inflammatory disorder with a strong genetic inheritance. Although more than 100 loci were reported through the genome-wide association study of European populations, the genetic underpinning of asthma in African American individuals remains largely elusive.ObjectiveWe aimed to identify genetic loci associated with asthma in African American individuals.MethodsThree cohorts were genotyped at the Children's Hospital of Philadelphia by using the Illumina single-nucleotide polymorphism array platform. Genotype imputation was performed by using the Trans-Omics for Precision Medicine (TOPMed) reference panel, which includes whole genome sequencing data from more than 100,000 individuals. A meta-analysis of 3 Children's Hospital of Philadelphia cohorts and 10 Consortium on Asthma among African Ancestry Populations in the Americas cohorts, totaling 19,628 subjects …

Background While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non‐European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans‐ethnic PRS for body mass index (BMI) through this relatively new international effort. Methods The polygenic risk score (PRS) model was developed, trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta‐analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis …

ImportanceSex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences ofAPOEare consistent across races and extend to theAPOEε2 allele.ObjectiveTo investigate whether sex and race modifyAPOEε4 and ε2 associations with cognition.Design, Setting, and ParticipantsThis genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022.Main Outcomes and MeasuresHarmonized composite scores for memory, executive function, and language were …

ObjectiveSuicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.MethodsThis study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression …

Leveraging linkage disequilibrium (LD) patterns as representative of population substructure enables the discovery of additive association signals in genome-wide association studies (GWASs). Standard GWASs are well-powered to interrogate additive models; however, new approaches are required for invesigating other modes of inheritance such as dominance and epistasis. Epistasis, or non-additive interaction between genes, exists across the genome but often goes undetected because of a lack of statistical power. Furthermore, the adoption of LD pruning as customary in standard GWASs excludes detection of sites that are in LD but might underlie the genetic architecture of complex traits. We hypothesize that uncovering long-range interactions between loci with strong LD due to epistatic selection can elucidate genetic mechanisms underlying common diseases. To investigate this hypothesis, we tested for …

Autoimmune diseases arise from atypical immune responses that attack self-tissue epitopes, and their development is intricately connected to the disruption of the JAK-STAT signaling pathway, where SOCS proteins play crucial roles. Conditions such as autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis exhibit immune system dysfunctions associated with JAK-STAT signaling dysregulation. Emerging therapeutic strategies utilize JAK-STAT inhibitors and SOCS mimetics to modulate immune responses and alleviate autoimmune manifestations. Although more research and clinical studies are required to assess their effectiveness, safety profiles, and potential for personalized therapeutic approaches in autoimmune conditions, JAK-STAT inhibitors and SOCS mimetics show promise as potential treatment options. This review explores the action, effectiveness, safety profiles, and future prospects of JAK inhibitors and SOCS mimetics as therapeutic agents for psoriasis, autoimmune uveitis, systemic lupus erythematosus, and autoimmune encephalitis. The findings underscore the importance of investigating these targeted therapies to advance treatment options for individuals suffering from autoimmune diseases.

Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and …

In accordance with the present invention, a method for detecting a propensity for developing eosinophilic esophagitis (EoE) in a subject in need thereof is provided. An exemplary method comprises detecting the presence of at least one genetic alteration in a target gene identified in said subject wherein if said genetic alteration is present, said patient has an increased risk for developing eosinophilic esophagitis, wherein said genetic alteration is present in a gene sequence from one or more loci of TMEM182, RAD50, SOX4, MATN2, PRKG1, RHOG, SHANK2, GPR12, RORA, SMAD3, GALNT1, CPNE4, URGCP, NAMPT, JAK2, and/or CCNY. The present inventors have discovered that such loci comprise single nucleotide polymorphisms (SNP) that indicate that the genetic alteration is present. In certain embodiments, the step of detecting the presence of said SNP comprises performing a process selected from the …

CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research and therapeutic development. While the exact role of CLEC16A in health and disease is still being elucidated, the gene plays a critical role in the regulation of autophagy, mitophagy, endocytosis, intracellular trafficking, immune function, and in biological processes such as insulin secretion and others that are important to cellular homeostasis. As shown in both human and animal modeling studies, CLEC16A hypofunction predisposes to both autoinflammatory phenotype and neurodegeneration. While the two are clearly related, further functional studies are needed to fully understand the mechanisms involved for optimized therapeutic interventions. Based on recent data, mitophagy-inducing drugs may be warranted, and such therapy should be tested in clinical trials as these drugs would tackle the underlying pathogenic mechanism (s) and could treat or prevent symptoms of autoimmunity and neurodegeneration in individuals with CLEC16A risk variants. Accordingly, interventions directed at reversing the dysregulated mitophagy and the consequences of loss of function of CLEC16A without activating other detrimental cellular pathways could present an effective therapy. This review presents the emerging role of CLEC16A in health and disease and provides an update on the disease processes that are attributed to variants located in the CLEC16A gene, which are responsible for autoimmune disorders and neurodegeneration with emphasis on how this information is being …

Background & AimsBiliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA.MethodsWe performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models.ResultsA GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p = 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p = 1.34E …

Objective We sought to develop and evaluate an electronic health record (EHR) genetic testing tracking system to address the barriers and limitations of existing spreadsheet-based workarounds. Materials and Methods We evaluated the spreadsheet-based system using mixed effects logistic regression to identify factors associated with delayed follow up. These factors informed the design of an EHR-integrated genetic testing tracking system. After deployment, we assessed the system in 2 ways. We analyzed EHR access logs and note data to assess patient outcomes and performed semistructured interviews with users to identify impact of the system on work. Results We found that patient-reported race was a significant predictor of documented genetic testing follow up, indicating a possible inequity in care. We implemented a CDS system including a …