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Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent–offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10−11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient–parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals ( P  = 1.57 × 10 −33 ). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease. In a cohort of patients with cerebral arachnoid cysts, multiomic analyses reveal de novo variants causing genetic neurodevelopmental conditions in up to 16% of cases, suggesting that surgery in these cases may not improve non-mass effect-related symptoms.

Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood developmental brain lesions. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trios) exomes, 152,898 human brain and mouse meningeal single-cell RNAseq transcriptomes, and natural language processing data of patient medical records. We found damaging de novo variants (DNVs) were highly enriched in patients with ACs compared to healthy individuals (P=1.57 × 10−33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes are enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data shed insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multi-omics approach to elucidate sporadic structural brain disease.

The emergence of the B.1.617.2 (Delta) variant of SARS-CoV-2 has led to increases in both infections and hospitalizations among adolescents. Little is known about the effectiveness of the BNT162b2 vaccine in adolescents in the general population, as opposed to a clinical trial population. To estimate the effectiveness of the BNT162b2 vaccine in adolescents aged 12 to 18 years. This was a matched case-control study among adolescents (aged 12-18 years) who had results from a SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test. Immunization histories, relevant clinical data, and RT-PCR test results were obtained from the Yale New Haven Health System's medical records between June 1, 2021, and August 15, 2021, when the Delta variant caused 92% of infections in Connecticut. Case participants were defined as adolescents who had a positive test result and an associated medical encounter. Control participants were defined as those who had a negative test result and were matched to a case participant by age, county of residence, and date of testing. Adolescents were defined as fully immunized if they had received 2 doses of vaccine at least 14 days before focal time. The primary outcome measured was SARS-CoV-2 infection confirmed by RT-PCR. The vaccine's effectiveness (VE) was estimated using matched odds ratios from conditional logistic regression models. Secondary measures included estimated VE by clinical symptoms, number of vaccine doses received, and elapsed time from immunization. A total of 6901 adolescents were tested for SARS-CoV-2. The final sample comprised 186 case participants and 356 matched control participants. The median age was 14 (IQR, 13-16) years, 262 (48%) identified as female, 81 (15%) as Black, 82 (15%) as Hispanic, and 297 (55%) as White. Overall, 134 (25%) were fully immunized (case participants, 10 [5%]; control participants, 124 [35%]). The median time between immunization and the SARS-CoV-2 test was 62 days (range, 17-129 days). Within 4 months of receiving 2 doses, VE against any infection was estimated to be 91% (95% CI, 80%-96%); against asymptomatic infection, 85% (95% CI, 57%-95%). Effectiveness after a single dose was estimated to be 74% (95% CI, 18%-92%). In this retrospective case-control study of US adolescents, 2 doses of BNT162b2 vaccine appeared to provide excellent protection for at least 4 months after immunization against both symptomatic and asymptomatic SARS-CoV-2 infections.

INTRODUCTION Congenital Hydrocephalus (CH) affects 1/1,000 live births and costs the US healthcare system over $2 billion annually. Surgical cerebrospinal fluid diversion exhibits high failure rates and substantial morbidity. Limited understanding of pathogenesis warrants identification of crucial genetic drivers underlying CH and their impact on brain development. METHODS Exome analysis of 381 radiographically-confirmed, neurosurgically-treated sporadic CH probands (including 232 case-parent trios) identified genes with rare de novo or transmitted mutations conferring disease risk. Transcriptome analyses identified mid-gestational brain modules and cell-types enriched for cohort-determined CH risk genes, known genes previously implicated in isolated and syndromic forms of CH, and risk genes of Autism Spectrum Disorder (ASD) and Developmental Disorder (DD). RESULTS Exome analysis reveals 9 high confidence genes and 55 probable risk genes harboring CH-linked mutations. Together, cohort-determined and known CH genes enrich in a single network (“yellow” module) associated with ASD and DD. Functional profiling of the yellow module yields terms of cell and neuronal differentiation, congenital anomalies of craniofacial development, and behavioral abnormalities. Cohort-determined and known CH genes together enrich in nascent migrating excitatory neurons and cycling mitotic progenitors, occupying earlier stages of differentiation than ASD- and DD-enriched cell-types. CONCLUSION Genetic drivers of CH converge in a neurodevelopmental network and in early neurogenic cell-types, implicating genetic disruption of early brain development as a primary patho-mechanism for a significant subset of CH patients. Transcriptional overlap with ASD and DD may explain persistence of these conditions in CH patients despite surgical intervention, while greater potency of CH-enriched neural precursors may account for increased frequency of structural brain abnormalities in CH than in ASD or DD alone.

Summary Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2. Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵22 Lead Contact * This version contains brain autopsy SARS-CoV-2 infection data.

Abstract Chronic obstructive pulmonary disease (COPD) is a common and progressive disease that is influenced by both genetic and environmental factors. For many years, knowledge of the genetic basis of COPD was limited to Mendelian syndromes, such as alpha-1 antitrypsin deficiency and cutis laxa, caused by rare genetic variants. Over the past decade, the proliferation of genome-wide association studies, the accessibility of whole-genome sequencing, and the development of novel methods for analyzing genetic variation data have led to a substantial increase in the understanding of genetic variants that play a role in COPD susceptibility and COPD-related phenotypes. COPDGene (Genetic Epidemiology of COPD), a multicenter, longitudinal study of over 10,000 current and former cigarette smokers, has been pivotal to these breakthroughs in understanding the genetic basis of COPD. To date, over 20 genetic loci have been convincingly associated with COPD affection status, with additional loci demonstrating association with COPD-related phenotypes such as emphysema, chronic bronchitis, and hypoxemia. In this review, we discuss the contributions of the COPDGene study to the discovery of these genetic associations as well as the ongoing genetic investigations of COPD subtypes, protein biomarkers, and post–genome-wide association study analysis.

Cigarette smoking (CS) impairs B-cell function and antibody production, increasing infection risk. The impact of e-cigarette use ('vaping') and combined CS and vaping ('dual-use') on B-cell activity is unclear. To examine B-cell receptor sequencing (BCR-seq) profiles associated with CS, vaping, and dual-use. BCR-seq was performed on blood RNA samples from 234 participants in the COPDGene study. We assessed multivariable associations of B-cell function measures (immunoglobulin heavy chain (IGH) subclass expression and usage, class-switching, V allele usage, and clonal expansion) with CS, vaping, and dual-use. We adjusted for multiple comparisons using the Benjamini-Hochberg method, identifying significant associations at 5% FDR and suggestive associations at 10% FDR. Among 234 non-Hispanic white (NHW) and African American (AA) participants, CS and dual-use were significantly positively associated with increased secretory IgA production, with dual-use showing the strongest associations. Dual-use was positively associated with class switching and B-cell clonal expansion, indicating increased B-cell activation, with similar trends in those only smoking or only vaping. The IGHV5-51*01 allele was increased in dual users. CS and vaping additively enhance B-cell activation, most notably in dual-users. CS and vaping are significantly associated to multiple alterations in B-cell function including increased class switching, clonal expansion, and a shift towards IgA-producing cell populations. These changes could be relevant to response to infection and vaccinations and merit further study.