Toxic epidermal necrolysis associated with pembrolizumab.

INTRODUCTION: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous drug eruptions characterized by epidermal detachment. Pembrolizumab is a monoclonal antibody that binds to the programmed death-1 receptor, and it has been associated with numerous cutaneous adverse side-effects, including Stevens-Johnson syndrome. CASE REPORT: We describe a 63-year-old male with metastatic lung adenocarcinoma who developed a rapidly progressing maculopapular rash three days after a first dose of pembrolizumab. On day 16, the rash affected more than 80% of body surface area with detachment of large sheets of necrolytic epidermis in 30-40% of body surface area. However, the patient only presented with mild mucosal involvement. Histopathologic examination of a skin biopsy showed a subepidermal blister with overlying prominent full thickness epidermal keratinocytic necrosis and a superficial perivascular infiltrate of lymphocytes. A toxic epidermal necrolysis secondary to pembrolizumab was then diagnosed. Management and outcome: In addition to supportive cares, the patient received corticosteroids and cyclosporine. The patient responded rapidly to the immunosuppressant therapy, and nearly complete re-epithelialization was achieved 24 days after the start of the reaction. DISCUSSION: In our review of the literature, 15 other cases of Stevens-Johnson syndrome/toxic epidermal necrolysis were reported with programmed death-1/programmed cell death ligand-1 inhibitors. To our knowledge, this is the first case of toxic epidermal necrolysis secondary to pembrolizumab published in the literature. The American Society of Clinical Oncology guidelines suggest that cyclosporine, in addition to corticosteroids, be initiated when toxic epidermal necrolysis is suspected. Clinicians should be aware of this rare dermatological emergency with the increasing use of pembrolizumab in oncology.

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.

11q24.2-25 micro-rearrangements in autism spectrum disorders: Relation to brain structures.

Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2-25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro-rearrangements (n=188), the patient had an increased volume of the sub-cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2-25 deletion on brain anatomy.

Bibliometric dataset (1995-2022) on green jobs: A comprehensive analysis of scientific publications.

The realm of green jobs presents a fertile ground for understanding the intersecting pathways between sustainable transition and the labor market. We have crafted a bibliometric dataset centered on this concept, amassing 414 articles from the Scopus and Web of Science databases, following a laid down protocol, PRISMA, spanning the period from 1995 to 2022. This endeavor aims to depict the dynamics, themes, and conceptual approaches shaping the discourse on green jobs. The dataset, structured around 13 descriptive variables such as authors, keywords, and cited references, is made available to researchers, institutions, and decision-makers to provide insight into the academic debates on ecological transition through the lens of employment, especially in the wake of a green economy. The potential for reutilizing these data is expansive. They can serve as a foundation for comparative analyses with the media and institutional portrayals of green jobs. Furthermore, the dataset can be enriched by integrating other forms of literature, such as books, chapters, or conference proceedings, while retaining the existing structure. This expansibility paves the way for a multidisciplinary and multilingual exploration, thereby enhancing the richness and diversity of possible analyses.

Characterizing weld pool surfaces from polarization state of thermal emissions.

In this Letter, a vision-based remote sensing methodology is proposed to measure the topography of weld pool surfaces from one single view. Thermal radiations emitted by the hot liquid metal at a wavelength within the arc plasma blind spectral window are acquired by a wavefront division polarimetric system. The refractive index of the liquid metal and the topography of the weld pool surface are inferred from the polarimetric state of the thermal radiations.

Morphological and Molecular Characterizations of Cochliomyia hominivorax (Diptera: Calliphoridae) Larvae Responsible for Wound Myiasis in French Guiana.

Myiasis is an ectoparasitic infection caused by the larvae of true flies (Diptera). We came across a rather rare case of myiasis in an immunocompetent 34-year-old man from French Guiana with advanced wound myiasis masquerading as cavitary myiasis and a history of cholesteatoma surgery in the left ear. The Diptera larvae responsible for the disease were isolated and identified using morphological and molecular approaches as Cochliomyia hominivorax. We underline the importance of this parasitosis as the second case of myiasis caused by C. hominivorax and the first case of wound myiasis in this overseas department of France and its incidence in pre-urban areas of the capital, Cayenne, in South America.

Dissecting the 22q13 region to explore the genetic and phenotypic diversity of patients with Phelan-McDermid syndrome.

SHANK3-related Phelan-McDermid syndrome (PMS) is caused by a loss of the distal part of chromosome 22, including SHANK3, or by a pathological SHANK3 variant. There is an important genetic and phenotypic diversity among patients who can present with developmental delay, language impairments, autism, epilepsy, and other symptoms. SHANK3, encoding a synaptic scaffolding protein, is deleted in the majority of patients with PMS and is considered a major gene involved in the neurological impairments of the patients. However, differences in deletion size can influence clinical features, and in some rare cases, deletions at the 22q13 locus in individuals with SHANK3-unrelated PMS do not encompass SHANK3. These individuals with SHANK3-unrelated PMS still display a PMS-like phenotype. This suggests the participation of other 22q13 genes in the pathogenesis of PMS. Here, we review the biological function and potential implication in PMS symptoms of 110 genes located in the 22q13 region, focusing on 35 genes with evidence for association with neurodevelopmental disorders, including 13 genes for epilepsy and 11 genes for microcephaly and/or macrocephaly. Our review is restricted to the 22q13 region, but future large-scale studies using whole genome sequencing and deep-phenotyping are warranted to develop predictive models of clinical trajectories and to target specific medical and educational care for each individual with PMS.

Phenotypic effects of genetic variants associated with autism.

While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Based on data from more than 13,000 individuals with autism and 210,000 undiagnosed individuals, we estimated the odds ratios for autism associated to rare loss-of-function (LoF) variants in 185 genes associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the correlates of these variants in individuals without a diagnosis of autism. We show that these variants are associated with a small but significant decrease in fluid intelligence, qualification level and income and an increase in metrics related to material deprivation. These effects were larger for autism-associated genes than in other LoF-intolerant genes. Using brain imaging data from 21,040 individuals from the UK Biobank, we could not detect significant differences in the overall brain anatomy between LoF carriers and non-carriers. Our results highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis and the need for more research to understand the association between these variants and sociodemographic factors, to best support individuals carrying these variants.

Voriconazole Sequestration During Extracorporeal Membrane Oxygenation for Invasive Lung Aspergillosis: A Case Report.

The increasing use of extracorporeal membrane oxygenation (ECMO) in critical care introduces new challenges with medication dosing. Voriconazole, a commonly used antifungal and the first-choice agent for the treatment of invasive aspergillosis, is a poorly water-soluble and highly protein-bound drug. Significant sequestration in ECMO circuits can be expected; however, no specific dosing recommendations are available. We report on the therapeutic drug monitoring and clinical evolution of a patient treated with voriconazole for invasive pulmonary aspergillosis while receiving ECMO therapy. Voriconazole trough levels were persistently low (<1 µg/mL) after initiation of ECMO despite additional loading doses and dose increases. Voriconazole dose had to be increased to 6.5 mg/kg three times daily to obtain therapeutic trough levels. The inability to achieve therapeutic levels of voriconazole for a prolonged period (a minimum of 9 days) while undergoing ECMO therapy is believed to have been a significant contributing factor in the patient's fatal outcome. Therapeutic trough levels of voriconazole cannot be guaranteed with standard dosing in patients undergoing ECMO and much higher doses may be necessary. Empirical use of higher doses and/or combination therapy may be reasonable and frequent therapeutic drug monitoring is mandatory.

Identification of Possible Causative Agents in a Polymedicated Patient Presenting With Toxic Epidermal Necrolysis.

PURPOSE: To present the pharmacological evaluation process in a case of a polymedicated patient presenting with toxic epidermal necrolysis (TEN). SUMMARY: A 75-year-old Caucasian polymedicated woman had been treated for hip pain with nonsteroidal anti-inflammatory drugs and pregabalin in the months preceding the apparition of an expanding papulo-erythematous rash. She had also started using new medicated eye drops for glaucoma. She presented to the emergency department of a regional hospital where all of her medications were stopped. The patient was transferred and admitted to a tertiary-care teaching hospital's specialized burn unit for significant cutaneous detachment. It was estimated that 70% to 80% of the body surface area was affected. Skin biopsy showed keratinocyte necrosis with a partial detachment of the epidermis leading to a diagnosis of TEN. The reaction ceased to progress 2 days after the discontinuation of her medications. A complete reepithelialization was objectified after 10 days. A series of steps were followed by the hospital pharmacist to determine which drugs were the most probable culprits. A complete pharmacological history was obtained and a timeline for medication use in the 3 months preceding rash apparition was established. A review of the literature was done to determine the drugs' relationships to Steven-Johnson syndrome or TEN. Using the algorithm of drug causality for epidermal necrolysis (ALDEN) score, it was determined that naproxen, pregabalin, and brinzolamide-timolol drops were all possible culprits. CONCLUSION: A systematic method for pharmacological evaluation of a polymedicated patient with TEN is presented. Naproxen, pregabalin, and brinzolamide-timolol drops were all retained as possible culprits.

Decreased phenol sulfotransferase activities associated with hyperserotonemia in autism spectrum disorders.

Hyperserotonemia is the most replicated biochemical abnormality associated with autism spectrum disorders (ASD). However, previous studies of serotonin synthesis, catabolism, and transport have not elucidated the mechanisms underlying this hyperserotonemia. Here we investigated serotonin sulfation by phenol sulfotransferases (PST) in blood samples from 97 individuals with ASD and their first-degree relatives (138 parents and 56 siblings), compared with 106 controls. We report a deficient activity of both PST isoforms (M and P) in platelets from individuals with ASD (35% and 78% of patients, respectively), confirmed in autoptic tissues (9 pineal gland samples from individuals with ASD-an important source of serotonin). Platelet PST-M deficiency was strongly associated with hyperserotonemia in individuals with ASD. We then explore genetic or pharmacologic modulation of PST activities in mice: variations of PST activities were associated with marked variations of blood serotonin, demonstrating the influence of the sulfation pathway on serotonemia. We also conducted in 1645 individuals an extensive study of SULT1A genes, encoding PST and mapping at highly polymorphic 16p11.2 locus, which did not reveal an association between copy number or single nucleotide variations and PST activity, blood serotonin or the risk of ASD. In contrast, our broader assessment of sulfation metabolism in ASD showed impairments of other sulfation-related markers, including inorganic sulfate, heparan-sulfate, and heparin sulfate-sulfotransferase. Our study proposes for the first time a compelling mechanism for hyperserotonemia, in a context of global impairment of sulfation metabolism in ASD.

A real-world experience of SARS-CoV-2 infection in a tertiary referral centre of Montréal: Unexpected low prevalence and low mortality.

BACKGROUND: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with chronic liver disease (CLD) and liver transplant (LT) recipients remains a concern. The aim of this study was to report the impact of coronavirus disease 2019 (COVID-19) infection among patients at the tertiary health care centre Centre hospitalier de l'Université de Montréal (CHUM) during the first wave of the SARS-CoV-2 pandemic. METHODS: This real-world, retrospective cohort included all patients admitted to our liver unit and/or seen as an outpatient with CLD with or without cirrhosis and/or LT recipients who tested positive to SARS-CoV-2 infection. Cases were considered positive as defined by the detection of SARS-CoV-2 by reverse-transcription polymerase chain reaction (RT-PCR) on nasopharyngeal swabs. RESULTS: Between April 1 and July 31, 2020, 5,637 were admitted to our liver unit and/or seen as outpatient. Among them, 42 were positive for SARS-CoV-2. Twenty-two patients had CLD without cirrhosis while 16 patients had cirrhosis at the time of the infection (13, 2, and 1 with Child-Pugh A, B, and C scores, respectively). Four were LT recipients. Overall, 15 of 42 patients (35.7%) were hospitalized; among them, 7 of 42 (16.7%) required respiratory support and 4 of 42 (9.5%) were transferred to the intensive care unit. Only 4 of 42 (9.5%) patients died: 2 with CLD without cirrhosis and 2 with CLD with cirrhosis. Overall survival was 90.5%. CONCLUSION: This real-world study demonstrates an unexpectedly low prevalence and low mortality in the context of SARS-CoV-2 infection among patients with CLD with or without cirrhosis and LT recipients.

Acute Severe Liver Injury Related to Long-Term Garcinia cambogia Intake.

Herbal and dietary supplements are frequently used as weight loss supplements. However, they account for 20% of drug-induced liver injury. Garcinia cambogia's (GC) active compound, hydroxycitric acid, can be found among those supplements. We report a 26-year-old woman who had been taking GC for 7 months when she presented with subacute liver failure and ultimately required a liver transplantation. This report highlights the risk of liver injury after long-term use of GC and demonstrates the importance of considering a close and prolonged monitoring of patients in a tertiary liver transplant center.

Development and validation of PART (Pharmacotherapy Assessment in Renal Transplant Patients) criteria to assess drug-related problems in an outpatient renal transplant population: A cross-sectional study.

Kidney transplant recipients are at risk of pharmacological interactions and adverse drug reactions. Community pharmacists are uniquely poised to detect and intervene in cases of drug-related problems. The aims of this study were to develop and validate a list of explicit criteria to be used by community pharmacists to assess drug-related problems in kidney transplant patients, and to assess their frequency and their determinants. First, we used a modified RAND method where a panel of experts established the PART (Pharmacotherapy Assessment in Renal Transplant Patient) criteria. Then, we performed a cross-sectional study in which we applied the PART criteria to 97 prevalent kidney transplant recipients followed at a single university-affiliated center. The final list of PART criteria included 70 drug-related problems and was reliable (kappa: 0.88). An average of 1.2 drug-related problems per patient was detected when the PART criteria were applied, with 68% of patients having at least 1 problem. This figure was 1.4 per patient using the expert judgment of renal transplant pharmacists who had no access to the PART list. The total number of medications taken was the only factor associated with the number of drug-related problems (ß: 0.27 for an increase of five medications, 95% CI 0.005, 0.547). The PART criteria provide a novel tool for community pharmacists to systematically detect drug-related problems in kidney transplant recipients.

Synesthesia & autistic features in a large family: Evidence for spatial imagery as a common factor.

BACKGROUND: Autism and synesthesia are neurodevelopmental conditions associated with variants of perceptual processing. They also share some genetic variants and include a large magnitude of intra-categorical variation: 60 types for synesthesia, as well as a spectrum for autism. In order to investigate the relationship between these two phenomena, we investigated the family of FC, an autistic individual who also possess savant abilities and synesthesia manifestations. METHOD: Autistic symptoms were assessed for the entire sample of participants entering the study (39 individuals) using the SRS. Participants above threshold were evaluated with standardized diagnostic tools. Synesthesia was explored in the entire participating sample using a self-reported questionnaire. Consistency tests were used for participants who reported synesthetic manifestations. RESULTS: In addition to FC, four individuals with ASD were detected. Fifteen participants self-reported synesthesia (15 sequence-space, 4 sound-shape, 4 day-color), among which nine sequence-space synesthetes satisfied the consistency criteria. Two participants possess both autism and synesthesia. CONCLUSION: This family illustrates the co-segregation of autism and synesthesia. This co-segregation is in favour of a partially overlapping genetic predisposition for both conditions, but also authorizes a large variety of manifestations in both conditions. The high prevalence of sequence-space synesthesia in this family strengthens the previous assumption that this form of synesthesia may be linked to autism. We discuss the potential role of spatial imagery in the development of this form of synesthesia and savant abilities.

Homozygous 2p11.2 deletion supports the implication of ELMOD3 in hearing loss and reveals the potential association of CAPG with ASD/ID etiology.

Autism spectrum disorder (ASD) is a set of neurodevelopmental conditions characterized by early-onset difficulties in social communication and unusually restricted, repetitive behavior and interests. Parental consanguinity may lead to higher risk of ASD and to more severe clinical presentations in the offspring. Studies of ASD families with high inbreeding enable the identification of inherited variants of this disorder particularly those with an autosomal recessive pattern of inheritance. In our study, using copy number variants (CNV) analysis, we identified a rare homozygous deletion in 2p11.2 region that affects ELMOD3, CAPG, and SH2D6 genes in a boy with ASD, intellectual disability (ID), and hearing impairment (HI). This deletion may reveal a new contiguous deletion syndrome in which ELMOD3, known to be implicated in autosomal recessive deafness underlies the HI of the proband and CAPG, member of actin regulatory proteins involved in cytoskeletal dynamic, an important function for brain development and activity, underlies the ASD/ID phenotype. A possible contribution of SH2D6 gene, as a part of a chimeric gene, to the clinical presentation of the patient is discussed. Our result supports the implication of ELMOD3 in hearing loss and highlights the potential clinical relevance of 2p11.2 deletion in autism and/or intellectual disability.

Both rare and common genetic variants contribute to autism in the Faroe Islands.

The number of genes associated with autism is increasing, but few studies have been performed on epidemiological cohorts and in isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 individuals with autism, 136 of their relatives and 185 non-autism controls. Data from SNP array and whole exome sequencing revealed that individuals with autism had a higher burden of rare exonic copy-number variants altering autism associated genes (deletions (p = 0.0352) or duplications (p = 0.0352)), higher inbreeding status (p = 0.023) and a higher load of rare homozygous deleterious variants (p = 0.011) compared to controls. Our analysis supports the role of several genes/loci associated with autism (e.g., NRXN1, ADNP, 22q11 deletion) and identified new truncating (e.g., GRIK2, ROBO1, NINL, and IMMP2L) or recessive deleterious variants (e.g., KIRREL3 and CNTNAP2) affecting autism-associated genes. It also revealed three genes involved in synaptic plasticity, RIMS4, KALRN, and PLA2G4A, carrying de novo deleterious variants in individuals with autism without intellectual disability. In summary, our analysis provides a better understanding of the genetic architecture of autism in isolated populations by highlighting the role of both common and rare gene variants and pointing at new autism-risk genes. It also indicates that more knowledge about how multiple genetic hits affect neuronal function will be necessary to fully understand the genetic architecture of autism.

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3.

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.

Erratum: Author Correction: A framework to identify contributing genes in patients with Phelan-McDermid syndrome.

[This corrects the article DOI: 10.1038/s41525-017-0035-2.].

Measuring and Estimating the Effect Sizes of Copy Number Variants on General Intelligence in Community-Based Samples.

Importance;: Copy number variants (CNVs) classified as pathogenic are identified in 10% to 15% of patients referred for neurodevelopmental disorders. However, their effect sizes on cognitive traits measured as a continuum remain mostly unknown because most of them are too rare to be studied individually using association studies. Objective: To measure and estimate the effect sizes of recurrent and nonrecurrent CNVs on IQ. Design, Setting, and Participants: This study identified all CNVs that were 50 kilobases (kb) or larger in 2 general population cohorts (the IMAGEN project and the Saguenay Youth Study) with measures of IQ. Linear regressions, including functional annotations of genes included in CNVs, were used to identify features to explain their association with IQ. Validation was performed using intraclass correlation that compared IQ estimated by the model with empirical data. Main Outcomes and Measures: Performance IQ (PIQ), verbal IQ (VIQ), and frequency of de novo CNV events. Results: The study included 2090 European adolescents from the IMAGEN study and 1983 children and parents from the Saguenay Youth Study. Of these, genotyping was performed on 1804 individuals from IMAGEN and 977 adolescents, 445 mothers, and 448 fathers (484 families) from the Saguenay Youth Study. We observed 4928 autosomal CNVs larger than 50 kb across both cohorts. For rare deletions, size, number of genes, and exons affect IQ, and each deleted gene is associated with a mean (SE) decrease in PIQ of 0.67 (0.19) points (P = 6 × 10-4); this is not so for rare duplications and frequent CNVs. Among 10 functional annotations, haploinsufficiency scores best explain the association of any deletions with PIQ with a mean (SE) decrease of 2.74 (0.68) points per unit of the probability of being loss-of-function intolerant (P = 8 × 10-5). Results are consistent across cohorts and unaffected by sensitivity analyses removing pathogenic CNVs. There is a 0.75 concordance (95% CI, 0.39-0.91) between the effect size on IQ estimated by our model and IQ loss calculated in previous studies of 15 recurrent CNVs. There is a close association between effect size on IQ and the frequency at which deletions occur de novo (odds ratio, 0.86; 95% CI, 0.84-0.87; P = 2.7 × 10-88). There is a 0.76 concordance (95% CI, 0.41-0.91) between de novo frequency estimated by the model and calculated using data from the DECIPHER database. Conclusions and Relevance: Models trained on nonpathogenic deletions in the general population reliably estimate the effect size of pathogenic deletions and suggest omnigenic associations of haploinsufficiency with IQ. This represents a new framework to study variants too rare to perform individual association studies and can help estimate the cognitive effect of undocumented deletions in the neurodevelopmental clinic.