Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations.

CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.

Neuromelanin levels in individuals with substance use disorders: A systematic review and meta-analysis.

Dopamine's role in addiction has been extensively studied, revealing disruptions in its functioning throughout all addiction stages. Neuromelanin in the substantia nigra (SN) may reflect dopamine auto-oxidation, and can be quantified using neuromelaninsensitive magnetic resonance imaging (neuromelanin-MRI) in a non-invasive manner.In this pre-registered systematic review, we assess the current body of evidence related to neuromelanin levels in substance use disorders, using both post-mortem and MRI examinations. The systematic search identified 10 relevant articles, primarily focusing on the substantia nigra. An early-stage meta-analysis (n = 6) revealed varied observations ranging from standardized mean differences of -3.55 to +0.62, with a pooled estimate of -0.44 (95 % CI = -1.52, 0.65), but there was insufficient power to detect differences in neuromelanin content among individuals with substance use disorders. Our gap analysis highlights the lack of sufficient replication studies, with existing studies lacking the power to detect a true difference, and a complete lack of neuromelanin studies on certain substances of clinical interest. We provide recommendations for future studies of dopaminergic neurobiology in addictions and related psychiatric comorbidities.

Cannabis cravings predict cigarette use in schizophrenia: a secondary analysis from two cannabis abstinence studies.

CLINICAL TRIAL NAME: Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on Cannabis Use and Cognitive Outcomes in SchizophreniaURL: www.clinicaltrials.gov; Registration Number: NCT03189810.

Association between cannabis use and symptom dimensions in schizophrenia spectrum disorders: an individual participant data meta-analysis on 3053 individuals.

Background: The association between cannabis use and positive symptoms in schizophrenia spectrum disorders is well documented, especially via meta-analyses. Yet, findings are inconsistent regarding negative symptoms, while other dimensions such as disorganization, depression, and excitement, have not been investigated. In addition, meta-analyses use aggregated data discarding important confounding variables which is a source of bias. Methods: PubMed, ScienceDirect and PsycINFO were used to search for publications from inception to September 27, 2022. We contacted the authors of relevant studies to extract raw datasets and perform an Individual Participant Data meta-analysis (IPDMA). Inclusion criteria were: psychopathology of individuals with schizophrenia spectrum disorders assessed by the Positive and Negative Syndrome Scale (PANSS); cannabis-users had to either have a diagnosis of cannabis use disorder or use cannabis at least twice a week. The main outcomes were the PANSS subscores extracted via the 3-factor (positive, negative and general) and 5-factor (positive, negative, disorganization, depression, excitement) structures. Preregistration is accessible via Prospero: ID CRD42022329172. Findings: Among the 1149 identified studies, 65 were eligible and 21 datasets were shared, totaling 3677 IPD and 3053 complete cases. The adjusted multivariate analysis revealed that relative to non-use, cannabis use was associated with higher severity of positive dimension (3-factor: Adjusted Mean Difference, aMD = 0.34, 95% Confidence Interval, CI = [0.03; 0.66]; 5-factor: aMD = 0.38, 95% CI = [0.08; 0.63]), lower severity of negative dimension (3-factor: aMD = -0.49, 95% CI [-0.90; -0.09]; 5-factor: aMD = -0.50, 95% CI = [-0.91; -0.08]), higher severity of excitement dimension (aMD = 0.16, 95% CI = [0.03; 0.28]). No association was found between cannabis use and disorganization (aMD = -0.13, 95% CI = [-0.42; 0.17]) or depression (aMD = -0.14, 95% CI = [-0.34; 0.06]). Interpretation: No causal relationship can be inferred from the current results. The findings could be in favor of both a detrimental and beneficial effect of cannabis on positive and negative symptoms, respectively. Longitudinal designs are needed to understand the role of cannabis is this association. The reported effect sizes are small and CIs are wide, the interpretation of findings should be taken with caution. Funding: This research did not receive any specific grant or funding. Primary financial support for authors was provided by Le Vinatier Psychiatric Hospital.

Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature.

SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.

Impaired protein hydroxylase activity causes replication stress and developmental abnormalities in humans.

Although protein hydroxylation is a relatively poorly characterized posttranslational modification, it has received significant recent attention following seminal work uncovering its role in oxygen sensing and hypoxia biology. Although the fundamental importance of protein hydroxylases in biology is becoming clear, the biochemical targets and cellular functions often remain enigmatic. JMJD5 is a "JmjC-only" protein hydroxylase that is essential for murine embryonic development and viability. However, no germline variants in JmjC-only hydroxylases, including JMJD5, have yet been described that are associated with any human pathology. Here we demonstrate that biallelic germline JMJD5 pathogenic variants are deleterious to JMJD5 mRNA splicing, protein stability, and hydroxylase activity, resulting in a human developmental disorder characterized by severe failure to thrive, intellectual disability, and facial dysmorphism. We show that the underlying cellular phenotype is associated with increased DNA replication stress and that this is critically dependent on the protein hydroxylase activity of JMJD5. This work contributes to our growing understanding of the role and importance of protein hydroxylases in human development and disease.

Does tobacco dependence worsen cannabis withdrawal in people with and without schizophrenia-spectrum disorders?

BACKGROUND AND OBJECTIVES: Rates of cannabis use disorder (CUD) are higher in people with schizophrenia than in the general population. Irrespective of psychiatric diagnosis, tobacco co-use is prevalent in those with CUD and leads to poor cannabis cessation outcomes. The cannabis withdrawal syndrome is well-established and increases cannabis relapse risk. We investigated whether cannabis withdrawal severity differed as a function of high versus no/low tobacco dependence and psychiatric diagnosis in individuals with CUD. METHOD: Men with CUD (N = 55) were parsed into four groups according to schizophrenia diagnosis and tobacco dependence severity using the Fagerstrom Test for Nicotine Dependence (FTND): men with schizophrenia with high tobacco dependence (SCT+, n = 13; FTND ≥ 5) and no/low tobacco dependence (SCT-, n = 22; FTND ≤ 4), and nonpsychiatric controls with high (CCT+, n = 7; FTND ≥ 5) and no/low (CCT-, n = 13; FTND ≤ 4) tobacco dependence. Participants completed the Marijuana Withdrawal Checklist following 12-h of cannabis abstinence. RESULTS: There was a significant main effect of tobacco dependence on cannabis withdrawal severity (p < .001). Individuals with high tobacco dependence had significantly greater cannabis withdrawal severity (M = 13.85 [6.8]) compared to individuals with no/low tobacco dependence (M = 6.49, [4.9]). Psychiatric diagnosis and the interaction effects were not significant. Lastly, cannabis withdrawal severity positively correlated with FTND (r = .41, p = .002). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Among individuals with CUD and high tobacco dependence, cannabis withdrawal severity was elevated twofold, irrespective of diagnosis, relative to individuals with CUD and no/low tobacco dependence. Findings from this study emphasize the importance of addressing tobacco co-use when treating CUD.

Neurocognitive moderation of repetitive transcranial magnetic stimulation (rTMS) effects on cannabis use in schizophrenia: a preliminary analysis.

Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment for cannabis use disorder in schizophrenia; however, gaps in the literature remain as to the potential role of neurocognitive functioning in treatment response. We evaluated the moderating role of select cognitive functions including baseline executive functioning, verbal memory, and sustained attention, and we explore the mediating role of changes in task performance on changes in cannabis use in both active and sham rTMS groups. Participants underwent high-frequency (20 Hz) rTMS applied to the bilateral dorsolateral prefrontal cortex 5x/week for 4 weeks. Weekly self-report of cannabis use and semi-quantitative urinary carboxy-tetrahydrocannabinol levels were recorded. A neurocognitive battery assessing verbal memory, visuospatial working memory, verbal working memory, sustained attention, delayed discounting, and complex planning was administered pre- and post-treatment. Better baseline performance on tasks assessing sustained attention, delayed discounting, and complex planning moderated the extent to which participants in the active group reduced cannabis use. There were no significant indirect pathways between treatment, changes in neuropsychological performance, and changes in cannabis use; however, active rTMS improved complex planning and sustained attention. These preliminary findings suggest that there is a moderating role of sustained attention, delayed discounting, and complex planning on the effects of rTMS on cannabis use. Further, mediation models suggest rTMS may exert direct effects on cannabis use independent of its effects on cognitive functioning in people with SCZ. Trial Registration: clinicaltrials.gov: NCT03189810.

Expanding the phenotypic spectrum of COLEC10-Related 3MC syndrome: A glimpse into COLEC10-Related 3MC syndrome in the Ashkenazi Jewish population.

Bi-allelic variants in COLEC11 and MASP1 have been associated with 3MC syndrome, a clinical entity made of up four rare autosomal recessive disorders: Carnevale, Mingarelli, Malpuech, and Michels syndromes, characterized by variable expression of facial dysmorphia, cleft lip/palate, postnatal growth deficiency, hearing loss, cognitive impairment, craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies. More recently, bi-allelic variants in COLEC10 have been described to be associated with 3MC syndrome. Syndromic features seen in 3MC syndrome are thought to be due to disruption of the chemoattractant properties that influence neural crest cell migration. We identified nine individuals from five families of Ashkenazi Jewish descent with homozygosity of the c.311G > T (p.Gly104Val) variant in COLEC10 and phenotype consistent with 3MC syndrome. Carrier frequency was calculated among 52,278 individuals of Jewish descent. Testing revealed 400 carriers out of 39,750 individuals of Ashkenazi Jewish descent, giving a carrier frequency of 1 in 99 or 1.01%. Molecular protein modeling suggested that the p.Gly104Val substitution alters local conformation. The c.311G > T (p.Gly104Val) variant likely represents a founder variant, and homozygosity is associated with features of 3MC syndrome. 3MC syndrome should be in the differential diagnosis for individuals with short stature, radioulnar synostosis, cleft lip and cleft palate.

De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations.

PURPOSE: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. METHODS: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. RESULTS: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. CONCLUSION: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.

Effects of 28 days of cannabis abstinence on cognition in major depressive disorder: A pilot study.

BACKGROUND AND OBJECTIVES: Cannabis is a widely used substance that may impair select cognitive domains, including attention and memory. Problematic cannabis use is a common clinical problem among patients with major depressive disorder (MDD). Few studies have investigated the effects of cannabis abstinence on cognition in MDD. Thus, our study aimed to determine whether a 28-day period of cannabis abstinence is associated with improvements in cognition in patients with MDD and comorbid cannabis use disorder (CUD). METHODS: We evaluated the effects of 28 days of cannabis abstinence on cognition in MDD patients with comorbid CUD facilitated by contingency management, motivational interviewing, psychoeducation, and coping-skills training (N = 11). Primary outcomes included Baseline to Day 28 changes in verbal memory and learning, while secondary outcomes included Baseline to Day 28 changes in working memory, visuospatial working memory (VSWM), visual search speed, mental flexibility, response inhibition, attention, manual dexterity, and fine motor movement. RESULTS: Eight participants (72.7%) met the pre-specified criteria for cannabis abstinence and three participants significantly reduced their cannabis use (≥90%). Visual search speed, selective attention, and VSWM improved over the study period. These improvements were not associated with changes in cannabis metabolite levels from baseline to endpoint. DISCUSSION AND CONCLUSIONS: Our findings suggest that 28 days of cannabis abstinence may improve select cognitive domains in patients with MDD and comorbid CUD. SCIENTIFIC SIGNIFICANCE: This is the first study to longitudinally examine the effects of cannabis on cognition in MDD. CLINICAL TRIAL: Effects of Cannabis Abstinence on Symptoms and Cognition in Depression (NCT03624933; https://www. CLINICALTRIALS: gov).

Heterozygous variants in CTR9, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder.

PURPOSE: CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher. METHODS: Exome sequencing was performed in all individuals. CTR9 variants were assessed through 3-dimensional modeling of the activated human transcription complex Pol II-DSIF-PAF-SPT6 and the PAF1/CTR9 complex. H3K4/H3K36 methylation analysis, mitophagy assessment based on tetramethylrhodamine ethyl ester perchlorate immunofluorescence, and RNA-sequencing in skin fibroblasts from 4 patients was performed. RESULTS: Common clinical findings were variable degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. For 11 CTR9 variants, de novo occurrence was shown. Three-dimensional modeling predicted a likely disruptive effect of the variants on local CTR9 structure and protein interaction. Additional studies in fibroblasts did not unveil the downstream functional consequences of the identified variants. CONCLUSION: We describe a neurodevelopmental disorder caused by (mainly) de novo variants in CTR9, likely affecting PAF1C function.

Dose-dependent effects of Varenicline on tobacco craving and withdrawal in tobacco smokers with and without schizophrenia.

BACKGROUND: People with schizophrenia (SCZ) have significantly higher tobacco smoking rates and lower quit rates than the general population. Varenicline, a partial agonist at α4ß2 nicotinic acetylcholine receptors (nAChRs) is an effective smoking cessation pharmacotherapy, however, investigation into its effects in SCZ are less well-studied and mechanisms may differ from non-psychiatric controls due to dysregulation in nAChR neurotransmission associated with SCZ. Here, we investigate whether Varenicline attenuates acute abstinence-induced increases in craving and withdrawal in participants with and without SCZ. METHODS: Following biochemically-verified overnight abstinence and subsequent smoking reinstatement, individuals with nicotine-dependence (n = 13 SCZ or schizoaffective; n = 12 controls) were assessed on the Minnesota Nicotine Withdrawal Scale (MNWS) and Tiffany Questionnaire for Smoking Urges (TQSU). Participants were pretreated in a double-blind, counterbalanced manner with Varenicline (0, 1 or 2 mg/day x 3 days) over three separate weeks. Data were analyzed using linear mixed-effects modelling and estimated marginal means. RESULTS: Robust effects of smoking abstinence were observed on TQSU and MNWS scores in SCZ and control participants. Relative to 1 mg, 2 mg/day of Varenicline attenuated abstinence-induced increases in craving (TQSU Factor 1 d=-0.47, p = .006; TQSU Factor 2 d=-0.42, p = .008) and withdrawal (MNWS d=-0.35, p = .03) in both groups. CONCLUSION: Our preliminary findings suggest that subacute Varenicline treatment reduces abstinence-induced craving and withdrawal in participants with and without SCZ. The efficacy of Varenicline on tobacco withdrawal and craving requires further study.

Investigating repetitive transcranial magnetic stimulation on cannabis use and cognition in people with schizophrenia.

Cannabis use disorder (CUD) occurs at high rates in schizophrenia, which negatively impacts its clinical prognosis. These patients have greater difficulty quitting cannabis which may reflect putative deficits in the dorsolateral prefrontal cortex (DLPFC), a potential target for treatment development. We examined the effects of active versus sham high-frequency (20-Hz) repetitive transcranial magnetic stimulation (rTMS) on cannabis use in outpatients with schizophrenia and CUD. Secondary outcomes included cannabis craving/withdrawal, psychiatric symptoms, cognition and tobacco use. Twenty-four outpatients with schizophrenia and CUD were enrolled in a preliminary double-blind, sham-controlled randomized trial. Nineteen participants were randomized to receive active (n = 9) or sham (n = 10) rTMS (20-Hz) applied bilaterally to the DLPFC 5x/week for 4 weeks. Cannabis use was monitored twice weekly. A cognitive battery was administered pre- and post-treatment. rTMS was safe and well-tolerated with high treatment retention (~90%). Contrast estimates suggested greater reduction in self-reported cannabis use (measured in grams/day) in the active versus sham group (Estimate = 0.33, p = 0.21; Cohen's d = 0.72), suggesting a clinically relevant effect of rTMS. A trend toward greater reduction in craving (Estimate = 3.92, p = 0.06), and significant reductions in PANSS positive (Estimate = 2.42, p = 0.02) and total (Estimate = 5.03, p = 0.02) symptom scores were found in the active versus sham group. Active rTMS also improved attention (Estimate = 6.58, p < 0.05), and suppressed increased tobacco use that was associated with cannabis reductions (Treatment x Time: p = 0.01). Our preliminary findings suggest that rTMS to the DLPFC is safe and potentially efficacious for treating CUD in schizophrenia.

Structural and functional brain recovery in individuals with substance use disorders during abstinence: A review of longitudinal neuroimaging studies.

BACKGROUND: Neuroimaging studies reveal structural and functional including neurochemical brain abnormalities in individuals with substance use disorders compared to healthy controls. However, whether and to what extent such dysfunction is reversible with abstinence remains unclear, and a review of studies with longitudinal within-subject designs is lacking. We performed a systematic review of longitudinal neuroimaging studies to explore putative brain changes associated with abstinence in treatment-seeking individuals with substance use disorders. METHODS: Following PRISMA guidelines, we examined articles published up to May 2021 that employed a neuroimaging technique and assessed neurobiological recovery in treatment-seeking participants at a minimum of two time-points separated by a period of abstinence (longer than 24 h apart) or significant reduction in drug use. RESULTS: Forty-five studies met inclusion criteria. Encouragingly, in this limited but growing literature, the majority of studies demonstrated at least partial neurobiological recovery with abstinence. Structural recovery appeared to occur predominantly in frontal cortical regions, the insula, hippocampus, and cerebellum. Functional and neurochemical recovery was similarly observed in prefrontal cortical regions but also in subcortical structures. The onset of structural recovery appears to precede neurochemical recovery, which begins soon after cessation (particularly for alcohol); functional recovery may require longer periods of abstinence. CONCLUSIONS: The literature is still growing and more studies are warranted to better understand abstinence-mediated neural recovery in individuals with substance use disorders. Elucidating the temporal dynamics between neuronal recovery and abstinence will enable evidence-based planning for more effective and targeted treatment of substance use disorders, potentially pre-empting relapse.

Common and gender-specific associations with cocaine use on gray matter volume: Data from the ENIGMA addiction working group.

Gray matter volume (GMV) in frontal cortical and limbic regions is susceptible to cocaine-associated reductions in cocaine-dependent individuals (CD) and is negatively associated with duration of cocaine use. Gender differences in CD individuals have been reported clinically and in the context of neural responses to cue-induced craving and stress reactivity. The variability of GMV in select brain areas between men and women (e.g., limbic regions) underscores the importance of exploring interaction effects between gender and cocaine dependence on brain structure. Therefore, voxel-based morphometry data derived from the ENIGMA Addiction Consortium were used to investigate potential gender differences in GMV in CD individuals compared to matched controls (CTL). T1-weighted MRI scans and clinical data were pooled from seven sites yielding 420 gender- and age-matched participants: CD men (CDM, n = 140); CD women (CDW, n = 70); control men (CTLM, n = 140); and control women (CTLW, n = 70). Differences in GMV were assessed using a 2 × 2 ANCOVA, and voxelwise whole-brain linear regressions were conducted to explore relationships between GMV and duration of cocaine use. All analyses were corrected for age, total intracranial volume, and site. Diagnostic differences were predominantly found in frontal regions (CD < CTL). Interestingly, gender × diagnosis interactions in the left anterior insula and left lingual gyrus were also documented, driven by differences in women (CDW < CTLW). Further, lower right hippocampal GMV was associated with greater cocaine duration in CDM. Given the importance of the anterior insula to interoception and the hippocampus to learning contextual associations, results may point to gender-specific mechanisms in cocaine addiction.

Emotion recognition in individuals with cocaine use disorder: the role of abstinence length and the social brain network.

RATIONALE: Emotion recognition is impaired in drug addiction. However, research examining the effects of cocaine use on emotion recognition yield mixed evidence with contradictory results potentially reflecting varying abstinence durations. OBJECTIVES: Therefore, we investigated emotion recognition and its neural correlates in individuals with cocaine use disorder (CUD) parsed according to abstinence duration. METHODS: Emotion recognition performance was compared between current cocaine users (CUD + , n = 28; cocaine-positive urine), short-term abstainers (CUD-ST, n = 23; abstinence < 6 months), long-term abstainers (CUD-LT, n = 20; abstinence ≥ 6 months), and controls (n = 45). A sample subset (n = 73) underwent structural magnetic resonance imaging to quantify regional gray matter volume (GMV) using voxel-based morphometry. RESULTS: CUD + demonstrated greater difficulty recognizing happiness than CUD-ST and controls, and sadness and fear compared to controls (p < 0.01). For fear, CUD-ST also performed worse than controls (p < 0.01), while no differences emerged between CUD-LT and controls. Whole-brain analysis revealed lower GMV in the bilateral cerebellum in CUD + compared to CUD-LT and controls; a similar pattern was observed in the amygdala (CUD + < CUD-LT) (pFWE < 0.01). Collapsed across all participants, poorer recognition for happiness was associated with lower right cerebellar GMV (pFWE < 0.05). CONCLUSIONS: Emotion recognition is impaired with current cocaine use, and selective deficits (in fear) may persist with up to 6 months of abstinence. Lower cerebellar GMV may underlie deficits in positive emotion recognition. Interventions targeting emotional-social-cognitive deficits, especially among active users, may enhance treatment success for individuals with CUD.

De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca2+ regulation.

Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 "trios" (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10-4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C Both RYR2 mutations are pathogenic (P = 1.7 × 10-7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10-7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3.

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.