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BackgroundMalformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants inGRIN1orGRIN2B, genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs.MethodsWe report the clinical, radiological and molecular features of 7 new patients and review data on 18 previously reported individuals with NMDAR-related MCDs. Neuropathological findings for two individuals with heterozygous variants inGRIN1are presented. We report the clinical and neuropathological features of one additional individual with homozygous pathogenic variants inGRIN1.ResultsHeterozygous variants inGRIN1andGRIN2Bwere associated with overlapping severe clinical and imaging features, including global developmental delay, epilepsy, diffuse dysgyria, dysmorphic basal ganglia and hippocampi. Neuropathological examination in two fetuses with heterozygousGRIN1variants suggests that proliferation as well as radial and tangential neuronal migration are impaired. In addition, we show that neuronal migration is also impaired by homozygousGRIN1variants in an individual with microcephaly with simplified gyral pattern.ConclusionThese findings expand our understanding of the clinical and imaging features of the ‘NMDARopathy’ spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients.

Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic copy number variants (CNVs). Because rare variants are primarily investigated in clinical cohorts, population-based estimates of their prevalence and penetrance are lacking. The authors determined the prevalence, penetrance, and NPD risk of pathogenic single-gene variants in a large health care system population.The authors analyzed linked genomic and electronic health record (EHR) data in a subset of 90,595 participants from Geisinger's MyCode Community Health Initiative, known as the DiscovEHR cohort. Loss-of-function pathogenic variants in 94 high-confidence NPD genes were identified through exome sequencing, and NPD penetrance was calculated using preselected EHR diagnosis codes. NPD risk was estimated using a case-control comparison of DiscovEHR participants with and without NPD diagnoses. Results from single-gene variant analyses were also compared with those from 31 previously reported pathogenic NPD CNVs.Pathogenic variants were identified in 0.34% of the DiscovEHR cohort and demonstrated a 34.3% penetrance for NPDs. Similar to CNVs, sequence variants collectively conferred a substantial risk for several NPD diagnoses, including autism, schizophrenia, and bipolar disorder. Significant NPD risk remained after participants with intellectual disability were excluded from the analysis, confirming the association with major psychiatric disorders in individuals without severe cognitive deficits.Collectively, rare single-gene variants and CNVs were found in1% of individuals in a large health care system population and play an important contributory role in mental health disorders. Diagnostic genetic testing for pathogenic variants among symptomatic individuals with NPDs could improve clinical outcomes through early intervention and anticipatory therapeutic support.

The establishment of an exotic pest may require displacing local species with a similar niche. The potential of Trogoderma granarium to displace Trogoderma inclusum was explored in a stored product setting. We performed direct competition experiments varying commodity and temperature over different durations. At nine weeks T. inclusum outproduced T. granarium on all commodities at any temperature. However the proportion of T. granarium versus T. inclusum was greater at 32 °C compared to 25 °C. The nine-week production of T. granarium was best on wheat, while rice was optimal for T. inclusum. After 25 weeks, when adults were used at the start of competition, T. inclusum maintained an advantage in the direct competition. If larvae were used to initiate the competition for 25 weeks, the two species coexisted well at 25 °C, but T. granarium nearly excluded T. inclusum at 32 °C. Thus T. inclusum performs better in competition over shorter intervals when resources are plentiful, but T. granarium can be more successful over longer time periods, particularly when late instar larvae are involved. The finding suggests a real threat of introductions of T. granarium larvae to establish populations within grain storage infrastructure where T. inclusum is common.

Trogoderma granarium Everts, the khapra beetle, native to the Indian subcontinent, is one of the world’s most destructive pests of stored food products. Early detection of this pest facilitates prompt response towards the invasion and prevents the need for costly eradication efforts. Such detection requires proper identification of T. granarium, which morphologically resembles some more frequently encountered, non-quarantine congeners. All life stages of these species are difficult to distinguish using morphological characters. Additionally, biosurveillance trapping can result in the capture of large numbers of specimens awaiting identification. To address these issues, we aim to develop an array of molecular tools to rapidly and accurately identify T. granarium among non-target species. Our crude, cheap DNA extraction method performed well for Trogoderma spp. and is suitable for downstream analyses including sequencing and real-time PCR (qPCR). We developed a simple quick assay usingrestriction fragment length polymorphism to distinguish between T. granarium and the closely related, congeneric T. variabile Ballion and T. inclusum LeConte. Based on newly generated and published mitochondrial sequence data, we developed a new multiplex TaqMan qPCR assay for T. granarium with improved efficiency and sensitivity over existing qPCR assays. These new tools benefit regulatory agencies and the stored food products industry by providing cost- and time-effective solutions to enhance the identification of T. granarium from related species. They can be added to the existing pest detection toolbox. The selection of which method to use would depend on the intended application.

We describe a clinical candidate molecule from a new series of glutamate N-methyl-d-aspartate receptor subunit 2B-selective inhibitors that shows enhanced inhibition at extracellular acidic pH values relative to physiologic pH. This property should render these compounds more effective inhibitors of N-methyl-d-aspartate receptors at synapses responding to a high frequency of action potentials, since glutamate-containing vesicles are acidic within their lumen. In addition, acidification of penumbral regions around ischemic tissue should also enhance selective drug action for improved neuroprotection. The aryl piperazine we describe here shows strong neuroprotective actions with minimal side effects in preclinical studies. The clinical candidate molecule NP10679 has high oral bioavailability with good brain penetration and is suitable for both intravenous and oral dosing for therapeutic use in humans. SIGNIFICANCE STATEMENT: This study identifies a new series of glutamate N-methyl-d-aspartate (NMDA) receptor subunit 2B-selective negative allosteric modulators with properties appropriate for clinical advancement. The compounds are more potent at acidic pH, associated with ischemic tissue, and this property should increase the therapeutic safety of this class by improving efficacy in affected tissue while sparing NMDA receptor block in healthy brain.

Background Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory. Results We describe a targeted ABA n = 1 patient trial with intrathecal MgSO4, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit. Conclusion Although the invasive nature of the trial necessitated a short-term, non-randomized, unblinded intervention, multimodal neurophysiologic monitoring indicated benefit, providing class II evidence in support of intrathecal MgSO4 for select forms of GRIN disorders.

The khapra beetle, Trogoderma granarium, is an important quarantine pest of stored-products. While it is not established in the North America, frequent interceptions highlight the need for treatments to eradicate isolated populations if they occur. Methyl bromide has long been the standard fumigant used for this purpose; however, increasing restrictions on its use necessitate the development of new treatment options. Here we evaluate a treatment for khapra beetle using a combination of sulfuryl fluoride (SF) and propylene oxide (PPO). Experiments were conducted to determine the most tolerant stages and the effective rates for each compound. Combination treatments using both products were then evaluated at several temperatures to determine effective doses for quarantine level control. The egg stage was by far the most tolerant to SF, requiring concentration × time (CT) products roughly 10-fold greater than the next most tolerant stage, diapausing larvae. Diapausing larvae were significantly more tolerant to SF than non-diapausing larvae in a recently collected ‘field’ strain, but not in a more than 30-yr-old ‘laboratory’ culture. PPO treatments were shown to completely control the egg stage at CTs greater than 155 hr-mgL-1 at both 10 and 20°C. Resulting combination treatments with initial dose rates of 96 and 40 mgL-1 at 10°C and 80 and 40 mgL-1 at 20°C are proposed for SF and PPO, respectively. These combination treatments utilize SF’s efficacy against the larval stage along with PPO’s superior ovicidal properties to provide enhanced treatment efficacy over each product alone against all life stages of khapra beetle.

ImportanceExome sequencing is a first-tier diagnostic test for individuals with neurodevelopmental disorders, including intellectual disability/developmental delay and autism spectrum disorder; however, this recommendation does not include cerebral palsy.ObjectiveTo evaluate if the diagnostic yield of exome or genome sequencing in cerebral palsy is similar to that of other neurodevelopmental disorders.Data SourcesThe study team searched PubMed for studies published between 2013 and 2022 using cerebral palsy and genetic testing terms. Data were analyzed during March 2022.Study SelectionStudies performing exome or genome sequencing in at least 10 participants with cerebral palsy were included. Studies with fewer than 10 individuals and studies reporting variants detected by other genetic tests were excluded. Consensus review was performed. The initial search identified 148 studies, of which 13 met inclusion criteria.Data Extraction and SynthesisData were extracted by 2 investigators and pooled using a random-effects meta-analysis. Incidence rates with corresponding 95% CIs and prediction intervals were calculated. Publication bias was evaluated by the Egger test. Variability between included studies was assessed via heterogeneity tests using the I2 statistic.Main Outcomes and MeasuresThe primary outcome was the pooled diagnostic yield (rate of pathogenic/likely pathogenic variants) across studies. Subgroup analyses were performed based on population age and on the use of exclusion criteria for patient selection.ResultsThirteen studies were included consisting of 2612 individuals with cerebral palsy. The overall diagnostic yield was 31.1% (95% CI, 24.2%-38.6%; I2 = 91%). The yield was higher in pediatric populations (34.8%; 95% CI, 28.3%-41.5%) than adult populations (26.9%; 95% CI, 1.2%-68.8%) and higher among studies that used exclusion criteria for patient selection (42.1%; 95% CI, 36.0%-48.2%) than those that did not (20.7%; 95% CI, 12.3%-30.5%).Conclusions and RelevanceIn this systematic review and meta-analysis, the genetic diagnostic yield in cerebral palsy was similar to that of other neurodevelopmental disorders for which exome sequencing is recommended as standard of care. Data from this meta-analysis provide evidence to support the inclusion of cerebral palsy in the current recommendation of exome sequencing in the diagnostic evaluation of individuals with neurodevelopmental disorders.

PURPOSE: Penetrance estimates of Birt-Hogg-Dubé (BHD)-associated cutaneous, pulmonary, and kidney manifestations are based on clinically ascertained families. In a healthcare system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) truncating variants in FLCN, which cause BHD, and the penetrance of BHD-related phenotypes. METHODS: Exomes from 135,990 patient-participants in Geisinger’s MyCode® cohort were assessed for P/LP truncating FLCN variants. BHD-related phenotypes were evaluated from electronic health records. Association between P/LP FLCN variants and BHD-related phenotypes was assessed by Firth’s logistic regression. RESULTS: P/LP truncating FLCN variants were identified in 35 individuals (1 in 3,234 unrelated individuals), 68.6% of whom had BHD-related phenotype(s) including: cystic lung disease (65.7%), pneumothoraces (17.1%), cutaneous manifestations (8.6%), and kidney cancer (2.9%). Four (11.4%) had prior clinical BHD diagnoses. CONCLUSION: In this healthcare population, the frequency of P/LP truncating FLCN variants is 60 times higher than the previously reported prevalence. Although most variant-positive individuals had BHD-related phenotypes, a minority were previously clinically diagnosed, likely because cutaneous manifestations, pneumothoraces, and kidney cancer were observed at lower frequencies than in clinical cohorts. Improved clinical recognition of cystic lung disease and education concerning its association with FLCN variants could prompt evaluation for BHD.

To describe interfacility transfer (IFT) intervals, transfer vehicle type, and levels of care in patients with large vessel occlusion (LVO) strokes transferred for emergent endovascular therapy (EVT).We included all patients transferred by a single IFT agency in the state of Indiana from July 1, 2018 to December 1, 2020 to a comprehensive stroke center in Indianapolis for emergent EVT. Data were collected from the transfer center electronic medical records and matched to IFT and receiving hospital data.Two hundred eighty-eight patients were included, of which 150 (52.0%) received EVT. The median call-to-needle interval (from call to the transfer center to EVT needle puncture) was 155.5 minutes (IQR 135.8-195.3). The median resource activation interval (call to the transfer center to IFT deployment) was 16 minutes (IQR 10-27 minutes); the median IFT response interval (call to IFT to arrival of the transferring unit) was 34 minutes (IQR 25-43 minutes); the median pre-transfer interval (call to the transfer center until departure from the sending hospital) was 60.4 minutes (IQR 47.1-72.6); and the median sending hospital interval at bedside was 25 minutes (IQR 20-30 minutes). Most patients (197, 68.4%) were sent via critical care rotor. Only 61 (21.2%) required interventions other than tissue plasminogen administration, such as titration of actively transfusing medications (e.g., nicardipine, propofol) (37 of 61, 59.7%), or intubation or ventilator management (25 of 61, 40.3%). Patients sent via critical care rotor had longer sending hospital intervals (26 minutes, IQR 22-32, vs 19 minutes, IQR 16-25; p 0.001) but shorter transfer intervals than those sent via critical care ground.At longer distances, rotor transport saved significant time specifically in the total IFT interval of patients with LVO strokes. Emphasizing processes to reduce the resource activation interval and the sending hospital interval may help reduce the overall time-to-EVT.

Developmental brain disorders (DBD), including autism spectrum disorder, intellectual disability, and schizophrenia, are clinically-defined and etiologically-heterogeneous conditions with a wide range of outcomes. Rare pathogenic copy number and single nucleotide genomic variants are among the most common known etiologies, with diagnostic yields approaching 50% for some DBD cohorts. Incorporating genetic testing into the care of adult patients with DBD, paired with targeted genetic counseling and family cascade testing, may increase self-advocacy and decrease stigma. In the long-term, breakthroughs in the understanding of DBD pathophysiology will hinge on the identification, engagement, and study of individuals with rare genetic DBD etiologies, consistent with successful precision medicine approaches to the treatment of cancer and cardiovascular disease.

There is a persistent gap in institutional-level graduation rates between U.S. Whites and underrepresented minorities (URM). This gap remains as graduation rates have increased for both Whites and URM. We tested whether these six-year graduation rate gaps among incoming undergraduate freshman cohorts were a function of institutional expenditures and financial aid. Our results were mixed. The gaps were much wider at institutions that spent more on academic and student services and who enrolled cohorts with higher average student loan amounts. Yet, these gaps between Whites and URM narrowed at institutions where students had larger average institutional and state/local grants. Our discussion centered on the changing financial context of higher education and the contributing roles of capital and institutional racial climate.

The transcription factor BMAL1/ARNTL is a non-redundant component of the clock pathway that regulates circadian oscillations of gene expression. Loss of BMAL1 perturbs organismal homeostasis and usually exacerbates pathological responses to many types of insults by enhancing oxidative stress and inflammation. Surprisingly, we observed improved locomotor recovery and spinal cord white matter sparing in Bmal1−/− mice after T9 contusive spinal cord injury (SCI). While acute loss of neurons and oligodendrocytes was unaffected, Bmal1 deficiency reduced the chronic loss of oligodendrocytes at the injury epicenter 6 weeks post SCI. At 3 days post-injury (dpi), decreased expression of genes associated with cell proliferation, neuroinflammation and disruption of the blood spinal cord barrier (BSCB) was also observed. Moreover, intraspinal extravasation of fibrinogen and immunoglobulins was decreased acutely at dpi 1 and subacutely at dpi 7. Subacute decrease of hemoglobin deposition was also observed. Finally, subacutely reduced levels of the leukocyte marker CD45 and even greater reduction of the pro-inflammatory macrophage receptor CD36 suggest not only lower numbers of those cells but also their reduced inflammatory potential. These data indicate that Bmal1 deficiency improves SCI outcome, in part by reducing BSCB disruption and hemorrhage decreasing cytotoxic neuroinflammation and attenuating the chronic loss of oligodendrocytes.

American Academy of Pediatrics (AAP) guidelines for children with Down syndrome (DS) include assessment for celiac disease (CD), although data to support this recommendation have been inconsistent. We determined the incidence of CD among children with DS in a population-based birth cohort of children born from 1976 to 2000 in Olmsted County, Minnesota. Individuals with karyotype-confirmed DS and CD (using diagnosis codes, positive serology, and duodenal biopsies) were identified. The incidence of CD in DS was compared with the published incidence of CD for Olmsted County residents (17.4 [95% confidence interval = 15.2-19.6] per 100 000 person-years). Among 45 individuals with DS from the birth cohort, 3 (6.7%) were identified with positive celiac serology and confirmatory biopsies at ages 9, 12, and 23 years, for an incidence of 325 per 100 000 person-years. Thus, individuals with DS have more than 18 times the incidence rate of CD compared with the general population, supporting the AAP guidelines.

Objectives Accurate estimates of autism spectrum disorder (ASD)–associated medical costs are essential for predicting future care needs, allocating resources, identifying best practices, and modeling cost-effectiveness. Most existing studies have either employed subjective cost data or ascertained ASD using self-reported or International Classification of Diseases–coded diagnoses. Such ascertainment is especially problematic for identifying milder ASD among older individuals never diagnosed with ASD. Methods This 1976 through 2000 population-based birth-cohort study was set in Olmsted County, Minnesota. ASD cases and age- and sex-matched unaffected controls were identified by applying uniform operational research criteria for ASD (using the guidelines of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision) after rigorous review of provider-linked medical and public, private, or home school records available for all members from birth to a maximum age of 21 years. Medical cost estimates for the 901 case-control pairs used line-item provider-linked billing data (including all payers) from 2003 through 2014 (ages 3-38 years). Outpatient pharmaceutical costs were unavailable. Temporal changes in diagnostic criteria, clinical practice, public awareness, and access were addressed by separating analyses into 5-year age group and 4-year calendar period cells. Unadjusted and adjusted (age and age plus co-occurring conditions) cost estimates were provided for cases, controls, and case-control differences. Additional factors (co-occurring conditions, percentage hospitalized, intellectual disability) were investigated using unadjusted descriptive analyses. Results Cell sample sizes ranged from 93 to 402 for age groups 3 through 19 years and from 45 to 395 for age groups 20 through 38 years. Unadjusted, age-adjusted, and fully adjusted medical costs were significantly higher for cases versus controls in 100% of cells for age groups 3 through 19 years and in 50% (unadjusted), 38% (age adjusted), and 12% (fully adjusted) of cells for age groups 20 through 38 years. Conclusions These unique estimates can help inform the construction of cost-effectiveness models; decisions by payers, providers, and policy makers; and predictions of lifetime costs.

Accumulating evidence in the literature suggests that oleic acid functions as a necromone across widely divergent insect taxa. The prevelance of this phenomenon has not been fully explored, and its application to pest management remains underdeveloped. Khapra beetle (KB), Trogoderma granarium, is a pest of stored grains, with larvae that can enter facultative diapause and remain cryptic in warehouses. Here, we examine how death affects oleic acid content of Trogoderma spp. cuticular extracts, and whether the compound causes a behavioral response. To assess the generalizability of patterns, many experiments were repeated with warehouse beetle (WB), Trogoderma variabile, and larger cabinet beetle (LCB), Trogoderma inclusum. Extracts of larvae that were first killed by being frozen had greater oleic acid content than those derived from live insects. Two-choice behavioral assays compared responses of solvent controls to these extracts, at both low (~ 2 µg) and high (68–131 µg) oleic acid content. The natural extracts also contained cuticular hydrocarbons and other unidentified chemicals. High oleic acid in the extracts repelled the larvae of all three species. Lower levels of oleic acid did not affect KB and LCB movement, but were attractive to WB. We also performed the assay using a large range of doses of oleic acid alone. At the lower doses, oleic acid had no effect on movement, but it became strongly repellant at higher doses, beginning at 100 µg. These results indicate that necromones may be an overlooked aspect of stored product insect biology, which if further researched could improve pest management.

A series of 27 meta-analyses was conducted to synthesize theoretical predictions, to date, of the relational turbulence model (RTM), which has informed relational turbulence theory (RTT). In line with theorized predictions, 12 random-effects meta-analyses (k = 9–15; n = 1,395–5,493) confirmed that RTM variables (i.e., self uncertainty, partner uncertainty, relationship uncertainty, and partner interference), on average, correlated with topic avoidance, depressive symptoms, and relationship satisfaction. An additional 15 random-effects meta-analyses (k = 4–41; n = 930–8,975) were conducted to pool an average correlation matrix among self uncertainty, partner uncertainty, relationship uncertainty, partner interference, partner facilitation, and relational turbulence. This pooled correlation matrix was used to test a meta-analytic structural equation model of the RTM commonly specified in the literature. Global and local fit statistics indicated the meta-analytic data fit the RTM well. Collectively, these results offer empirical and theoretical evidence for the RTM across nearly 2 decades of research and provide insights for future scholarship guided by the axioms and propositions of RTT.

This study explored the relationship between the four dimensions of students’ feedback orientation (i.e., utility, retention, confidentiality, and sensitivity) and the four dimensions of students’ ...

The Anastrepha fraterculus (Wiedemann) complex is currently comprised of at least eight morphotypes, including several that are likely to be described as new species. It is critical to evaluate whether the morphotypes differ in tolerance to phytosanitary treatments. Temperatures from 0 to 3°C are used as a phytosanitary treatment for some commodities exported from the region and at risk of infestation by the A. fraterculus complex. Description of A. fraterculus morphotypes as new species could result in the annulation of phytosanitary treatment schedules for the new species. This study compared the relative cold tolerance of five populations from three morphotypes of the A. fraterculus complex: Andean, Peruvian, and Brazilian-1. Both a laboratory and wild strain of the Brazilian-1 morphotype were studied. Differences in mortality of third instars of the five A. fraterculus populations reared on nectarines were observed only with short treatment durations at temperatures ranging from 1.38 ± 0.04°C to 1.51 ± 0.08°C (mean ± SEM). Estimated times to achieve the LT99.99682 (probit 9) showed that Brazilian-1 wild, Brazilian-1 laboratory, and Cusco population were the most cold tolerant, followed by Andean and Peruvian, the least cold tolerant morphotype (i.e., Brazilian-1 wild = Brazilian-1 laboratory = Cusco population > Andean > Peruvian). These findings suggest that the current cold treatment schedules of 15 d at ≤ 1.11°C and 17 d at ≤ 1.67°C can be applied as cold treatments to any potential new species that may arise from the A. fraterculus complex.

Solid wood packaging material (WPM) is widely recognized as a high-risk pathway for transport and potential introduction of wood-boring insects, including longhorned beetles in the family Cerambycidae. These beetles also are occasionally imported in finished wood products, such as furniture and decorative items. A targeted effort to identify wood borers intercepted as larvae in WPM at U.S. ports between 2012 and 2018 revealed that one of the most frequently intercepted species was Trichoferus campestris (Faldermann), a cerambycid native to Asia. Trichoferus campestris is a pest of quarantine concern in the United States, Canada, and Europe. The establishment risk of this beetle in the United States is high because of its frequent introduction through multiple pathways and its potential to inhabit natural and urban forests as well as agricultural systems. In this study, we compiled port interception and detection data to examine risk based on historical introductions and pathways. We tested whether the intended destination of cargo intercepted with T. campestris-infested WPM can be used as a predictor of inland introductions, assuming that individuals of T. campestris are likely to be moved through established trade routes between export–import partners. We also developed maps to predict likely areas of introduction and establishment in the United States based on pathway analysis and climate suitability data. The maps will enable informed prioritization of resources in pest surveillance, and may serve as models for other wood borers identified in the WPM and wood products pathway.

BackgroundA neurodevelopmental syndrome was recently reported in four patients withSOX4heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome.MethodsWe newly identified 17 patients withSOX4variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients’ phenotypes.ResultsAll variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including theSOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS.ConclusionThese findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due toSOX4haploinsufficiency in neurogenesis and multiple other developmental processes.

PurposeCurrent penetrance estimates of Birt-Hogg-Dubé (BHD)-associated cutaneous, pulmonary, and renal manifestations are based on clinically ascertained families. In a healthcare system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) variants in the FLCN gene, which cause BHD, and the penetrance of BHD-related phenotypes.MethodsExomes from 135,990 patient-participants in Geisinger’s MyCode® cohort were assessed for P/LP FLCN variants. BHD-related phenotypes were evaluated from electronic health records. Association between FLCN P/LP variants and BHD-related phenotypes were assessed by Firth’s logistic regression.ResultsP/LP FLCN variants were identified in 35 (1 in 3,234) individuals, 68.6% of whom had BHD-related phenotype(s) including: cystic lung disease (65.7%); pneumothoraces (17.1%); cutaneous manifestations (8.6%); and renal cancer (2.9%). Only four (11.4%) were clinically diagnosed with BHD.ConclusionIn this healthcare population, the frequency of P/LP FLCN variants is 60 times higher than the previously reported prevalence. Although most variant-positive individuals had BHD-related phenotypes in the EHR, a minority were clinically diagnosed with BHD, likely because cutaneous manifestations, pneumothoraces, and renal cancer were observed at lower frequencies than clinical cohorts. Improved clinical recognition of cystic lung disease and education concerning its association with FLCN variants could prompt evaluation for BHD.

OBJECTIVES We aimed to describe the intellectual ability and ratio of boys to girls with average or higher IQ within autism spectrum disorder (ASD) cases identified in a population-based birth cohort. We hypothesized that research-identified individuals with ASD would be more likely to have average or higher IQ, compared to clinically diagnosed ASD. We also hypothesized the male to female ratio would decrease as the definition of ASD broadened. METHODS ASD incident cases were identified from 31 220 subjects in a population-based birth cohort. Research-defined autism spectrum disorder, inclusive criteria (ASD-RI) was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, autistic disorder (AD), Asperger Disorder, and pervasive developmental disorder not otherwise specified criteria. Research-defined autism spectrum disorder, narrow criteria (ASD-RN) was a narrower definition based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision AD criteria. Clinical diagnoses of ASD were abstracted from medical and school records. Intellectual ability was based on the last IQ score or on documented diagnoses of intellectual disability if no scores available. Average or higher IQ was defined as IQ ≥86. RESULTS A total of 59.1% of those with ASD-RI (n = 890), 51.2% of those with ASD-RN (n = 453), and 42.8% of those with clinically diagnosed autism spectrum disorder (n = 187) had average or higher IQ. Within the ASD-RI and ASD-RN groups, boys were more likely than girls to have an average or higher IQ (62.0% vs 51.3% [P = .004] and 54.1% vs. 42.5% [P = .03], respectively). CONCLUSION Our data suggest that nearly half of individuals with ASD have average or higher IQ. Boys with ASD are more likely to have average or higher IQ than girls. Patients with ASD and higher IQ remain at risk for not being identified.