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Pegunigalsidase alfa, a PEGylated α-galactosidase A enzyme replacement therapy (ERT) for Fabry disease, has a longer plasma half-life than other ERTs administered intravenously every 2 weeks (E2W). BRIGHT (NCT03180840) was a phase III, open-label study in adults with Fabry disease, previously treated with agalsidase alfa or beta E2W for ≥3 years, who switched to 2 mg/kg pegunigalsidase alfa every 4 weeks (E4W) for 52 weeks. Primary objective assessed safety, including number of treatment-emergent adverse events (TEAEs). Thirty patients were enrolled (24 males); 23 previously received agalsidase beta. Pegunigalsidase alfa plasma concentrations remained above the lower limit of quantification throughout the 4-week dosing interval. Thirty-three of 182 TEAEs (in 9 patients) were considered treatment-related; all were mild/moderate. No patients developed de novo anti-drug antibodies (ADAs). In the efficacy analysis (n = 29), median (inter-quartile range) eGFR change from baseline over 52 weeks was -1.9 (-5.9; 1.8) mL/min/1.73 m 2 (n = 28; males [n = 22]: -2.4 [-5.2; 3.2]; females [n = 6]: -0.7 [-9.2; 2.0]). Overall, median eGFR slope was -1.9 (-8.3; 1.9) mL/min/1.73 m 2 /year (ADA-negative [n = 20]: -1.2 [-6.4; 2.6]; ADA-positive [n = 9]: -8.4 [-11.6; -1.0]). Lyso-Gb3 concentrations were low and stable in females, with a slight increase in males (9/24 ADA-positive). The BRIGHT study results suggest that 2 mg/kg pegunigalsidase alfa E4W is tolerated well in stable adult patients with Fabry disease. Due to the low number of patients in this study, more research is needed to demonstrate the effects of pegunigalsidase alfa given E4W. Further evidence, outside of this clinical trial, should be factored in for physicians to prolong the biweekly ERT intervals to E4W. TAKE-HOME MESSAGE: Treatment with 2 mg/kg pegunigalsidase alfa every 4 weeks could offer a new treatment option for patients with Fabry disease., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care., Competing Interests: Declaration of Competing Interest No honorarium, grant, or other form of payment was received to produce the manuscript. LAA is a consultant to Biogen, Takeda Pharmaceuticals, Orchard Therapeutics, is a site subinvestigator for the Takeda trial, and serves on the scientific advisory board of Cure MLD and MLD Foundation; JLB is a site principal investigator for the Takeda SHP611 trial; JJB has received consulting fees from Sobi, Omeros, Bluebird Bio, Sanofi, SmartImmune, Merck and Bluerock; EM has no conflicts of interest to disclose; RAN has no conflicts of interest to disclose; JAB is a site principal investigator for the Takeda SHP611 trial; AB is site subinvestigator for the Takeda SHP611 trial and received travelling support by Orchard-Tx; BB is a site principal investigator for the Takeda SHP611 trial and is a consultant to Aro, AlltRNA, Orchard Therapeutics, Astella, Passage Bio, Biomarin, PTC Therapeutics, JCR Pharma, Takeda; received honoraria from Astra Zeneca, Biomarin, Chiesi, Horizon, JCR Pharma; grant funding from Biomarin Pharmaceutical, Takeda, Homology Medicines, Denali Therapeutics, Sangamo, JCR Pharma, and Ultragenyx; AD has participated in an advisory board organized by Orchard Therapeutics; FE has <1% equity in Swan Bio, and royalties from AAV9 license for AMN; receives consulting fees from Leal Therapeutics, Swan Bio, Ionis, Minoryx, UptoDate, Origen, Takeda Therapeutics and Third Rock Ventures; founder and consultant of Swan Bio and serves on the chair on the advisory board of European Leukodystrophy Association, and as a board member at United Leukodystrophy Foundation; EE has participated in several advisory boards arranged by Orchard Therapeutics; LE serves on the advisory board for Ionis pharmaceuticals; ME is Chief Medical Officer at Forge Biologics; AF receives research support from SwanBio, Autobahn Therapeutics, Poxel Therapeutics, Vertex Pharmaceuticals, and Maryland Stem Cell Research Fund, was a Data and Safety Monitoring Board (DSMB) member for BlueBird Bio, and coinvented a patent currently licensed to Ashvattha; JF is a consultant for GeneDx, Educational Consultant on the Impact of Exome and Genome Sequencing in Well-Phenoptyped Populations and is Chair of the Maryland Secretary's Advisory Council on Hereditary and Congenital Disorders; AG has received payment or honoraria from Spark Therapeutics and Orchard Therapeutics, consulting fees from Takeda; chair of the MN Rare Disease Advisory Council and the Clinical and Laboratory Standards Institute; SK is a clinical trial site principal investigator for Ionis and was a consultant for Veristat; MCP is the site principal investigator for clinical trials funded by Azafaros, Glycomine, Idorsia, Maggie's Pearl, Takeda, and Zevra, and has consulted for Azafaros, Takeda, and Zevra; serves as editor in chief of the Journal of Child Neurology and an editor for JIMD, and royalties as section editor for up to date; PO is a consultant to Orchard Therapeutics, serves on a DSMB for Ionis, and has clinical trial support from Immusoft and Allovir; JOM is a consultant to Novoglia and site principal investigator for Vigil Neuroscience; JDS is a consultant to Biogen and Cycle Pharma; LS is a consultant to Vico Therapeutics and a site principal investigator for trials of Vigil Neuroscience, Stealth Biotherapeutics and PTC Therapeutics; CS is PI of the Takeda clinical trial and consultant for Orchard Therapeutics; INS has no conflicts of interest to disclose; DR is site PI for the Takeda trial; JPR has no conflicts of interest to disclose; KVH is a consultant for Bluebird bio and Poxel, a site PI for trials funded by Minoryx, Bluebird bio, IONIS and a trial advisor for Calico; MW has received research support from Abeona Therapeutics, Alexion Pharmaceuticals, the Ara Parseghian Medical Research Foundation, BioMarin Pharmaceutical, Cure Sanfilippo Foundation, Dana's Angels Research Trust, Firefly Fund, Mirum Pharma, Noah's Hope, Orchard Therapeutic, Passage Bio, Sanofi Genzyme, Sio Gene Therapies, Takeda Pharmaceutical, Travere Therapeutics, and Ultragenyx Pharmaceutical; has received consulting fees from Sanofi Genzyme; AZ is a site subinvestigator for the Takeda trial; FF is License holder of OTL-200, I Orchard Therapeutics trial, advisor Orchard, Takeda, funding Telethon Foundation, GSK, Orchard; LL has no conflicts of interest to disclose; AV is an advisor to Takeda, Passagebio, Orchard; and is site PI Takeda trial., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Fabry disease (FD) is a rare lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding α-galactosidase (α-Gal)-A. We evaluated long-term safety/efficacy of pegunigalsidase alfa, a novel PEGylated α-Gal-A enzyme replacement therapy (ERT) now approved for FD., Methods: In a phase-1/2 dose-ranging study, 15 ERT-naive adults with FD completed 12 months of pegunigalsidase alfa and enrolled in this 60-month open-label extension of 1 mg/kg pegunigalsidase alfa infusions every 2 weeks., Results: Fifteen patients enrolled (8 males; 7 females); 10 completed ≥48 months (60 months total treatment), and 2 completed 60 months (72 months total treatment). During treatment, most treatment-emergent adverse events were mild/moderate in severity and all infusion-related reactions were mild/moderate in severity. Four patients were transiently positive for anti-pegunigalsidase alfa IgG. Patients showed continuous reduction in plasma lyso-Gb3 concentrations with mean (standard error) reduction of 76.1 [25.1] ng/mL from baseline to month 24. At 60 months, the estimated glomerular filtration rate slope was comparable to that observed in patients treated with other ERTs. Cardiac function assessments revealed stability; no cardiac fibrosis was observed., Conclusion: In this first long-term assessment of pegunigalsidase alfa administration in patients with FD, we found favorable safety/efficacy. Our data suggest long-term continuous benefits of pegunigalsidase alfa treatment in adults with FD., Competing Interests: Conflict of Interest Derralynn Hughes has received speaker’s honoraria from Amicus Therapeutics, Takeda, Sanofi, Freeline, Protalix, and Idorsia. Derlis Gonzalez has been or is currently involved in clinical trials with Takeda, Protalix, and mAbxience. Gustavo Maegawa has received grants, personal and consultant fees from Sanofi; grants from Pfizer Inc.; personal fees from Sio Gene Therapies; grants from NIH/NINDS, and personal fees from NIH/CSR. John A. Bernat receives research support from Avrobio, BioMarin Pharmaceutical, Chiesi Farmaceutici, Idorsia Pharmaceuticals, Pfizer, Protalix Biotherapeutics, Sangamo Therapeutics, Sanofi, Takeda, and Travere Therapeutics; has received a speaker honorarium from the Fabry Support and Information Group; and has participated in advisory boards for Chiesi USA, Sanofi, and Takeda. Myrl Holida has received speaker honoraria from Protalix and Chiesi and has participated in advisory boards for Amicus and Sanofi. Pilar Giraldo has been involved in premarketing studies with Genzyme, Protalix, and Idorsia and has received grants from Sanofi and Takeda; monies received for these activities have been deposited into the Spanish Foundation for the Study and Treatment of Gaucher Disease (FEETEG) to contribute to the development of research in lysosomal storage disorders. Mohamed G. Atta declares no conflicts of interest. Sari Alon is a full-time employee of Protalix. Raul Chertkoff and Einat Brill Almon were full-time employees of Protalix at the time of study conduct and are now consultants to Protalix. Rossana Rocco is a full-time employee of Chiesi. Ozlem Goker-Alpan has conducted contracted research with Amicus, Freeline, Genentech, Protalix, Sangamo, Sanofi, Takeda, 4DMT, Avrobio; received consulting fees from Amicus, Sanofi, Takeda, Sangamo, 4DMT, Avrobio; served on advisory boards for Amicus, Sanofi, Takeda, Sangamo, 4DMT, Avrobio; and participated in speakers’ bureaus for Sanofi, Takeda., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Gaucher disease (GD) is an autosomal recessive inherited lysosomal storage disease that often presents in early childhood and is associated with damage to multiple organ systems. Many challenges associated with GD diagnosis and management arise from the considerable heterogeneity of disease presentations and natural history. Phenotypic classification has traditionally been based on the absence (in type 1 GD) or presence (in types 2 and 3 GD) of neurological involvement of varying severity. However, patient management and prediction of prognosis may be best served by a dynamic, evolving definition of individual phenotype rather than by a rigid system of classification. Patients may experience considerable delays in diagnosis, which can potentially be reduced by effective screening programs; however, program implementation can involve ethical and practical challenges. Variation in the clinical course of GD and an uncertain prognosis also complicate decisions concerning treatment initiation, with differing stakeholder perspectives around efficacy and acceptable cost/benefit ratio. We review the challenges faced by physicians in the diagnosis and management of GD in pediatric patients. We also consider future directions and goals, including acceleration of accurate diagnosis, improvements in the understanding of disease heterogeneity (natural history, response to treatment, and prognosis), the need for new treatments to address unmet needs for all forms of GD, and refinement of the tools for monitoring disease progression and treatment efficacy, such as specific biomarkers., Competing Interests: Declaration of Competing Interest NJW has consulted for Pfizer, Sanofi Genzyme and Takeda, has participated in speaking engagements for Sanofi Genzyme, and is a member of the data safety monitoring board for AVROBIO. OG-A has served on advisory boards and received consulting fees from 4DMT, Amicus Therapeutic, Sangamo Therapeutics, Sanofi Genzyme and Takeda, has research contracts with 4DMT, Amicus Therapeutics, AVROBIO, Freeline Therapeutics, Genentech, Protalix BioTherapeutics, Sangamo Therapeutics, Sanofi Genzyme and Takeda, and has participated in a speaker bureau for Sanofi Genzyme and Takeda. PSK has received research/grant support from Pfizer, Sanofi Genzyme and Takeda, has received consulting fees and honoraria from Sanofi Genzyme and Takeda, and is a member of the Gaucher Disease Registry Advisory Board for Sanofi Genzyme and the Advisory Board for Takeda. NL has participated in advisory boards and clinical trials for Amicus Therapeutics, Pfizer, Protalix BioTherapeutics, Sanofi Genzyme and Shire (a Takeda company). TAB is a member of the American Gaucher Disease Registry Board. He has participated in advisory board meetings for and received research funding, travel reimbursement, and honoraria for speaking from Sanofi Genzyme and Takeda. JAB receives research support from AVROBIO, BioMarin Pharmaceutical, Idorsia Pharmaceuticals, Pfizer, Protalix BioTherapeutics, Sangamo Therapeutics, Sanofi Genzyme and Takeda and has served on advisory boards for Sanofi Genzyme and Takeda. PG has participated in advisory boards and clinical trials for BioMarin Pharmaceutical, Pfizer, Sanofi Genzyme and Shire (a Takeda company) and is on the speaker bureau for Sanofi Genzyme. NH has nothing to disclose. HP has participated in advisory boards and/or speaking engagements and/or clinical trials for Alexion Pharmaceuticals, Amicus Therapeutics, AVROBIO, Sanofi Genzyme and Takeda. CP has consulted for Takeda and has participated in a speaker bureau for Sanofi Genzyme. DV has nothing to disclose. RRP is a full-time employee of Takeda and a stockholder of Takeda Pharmaceuticals Company Limited. EW is a full-time employee of Takeda and a stockholder of Takeda Pharmaceuticals Company Limited. CF has served as an advisor or consultant for Horizon Therapeutics, Orphan Technologies, Recordati, Sanofi Genzyme, Shire (a Takeda company) and Swedish Orphan Biovitrum. He has received grants for clinical research from Homology Medicines, Orphan Technologies, Passage Bio, REGENXBIO, Sanofi Genzyme, Takeda and Vtesse., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs., (© The Author(s) 2021. Published by Oxford University Press.)

Purpose: Widespread, quality genomics education for health professionals is required to create a competent genomic workforce. A lack of standards for reporting genomics education and evaluation limits the evidence base for replication and comparison. We therefore undertook a consensus process to develop a recommended minimum set of information to support consistent reporting of design, development, delivery, and evaluation of genomics education interventions., Methods: Draft standards were derived from literature (25 items from 21 publications). Thirty-six international experts were purposively recruited for three rounds of a modified Delphi process to reach consensus on relevance, clarity, comprehensiveness, utility, and design., Results: The final standards include 18 items relating to development and delivery of genomics education interventions, 12 relating to evaluation, and 1 on stakeholder engagement., Conclusion: These Reporting Item Standards for Education and its Evaluation in Genomics (RISE2 Genomics) are intended to be widely applicable across settings and health professions. Their use by those involved in reporting genomics education interventions and evaluation, as well as adoption by journals and policy makers as the expected standard, will support greater transparency, consistency, and comprehensiveness of reporting. Consequently, the genomics education evidence base will be more robust, enabling high-quality education and evaluation across diverse settings.

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2., (© 2020 Wiley Periodicals LLC.)

Background: As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate., Methods: Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES., Results: Overall, 30% of patients who underwent CES had an identified pathogenic mutation. The most common phenotypes were developmental delay (83%), neuromuscular system abnormalities (81%), and multiple congenital anomalies (42%). In all, 67% of patients had a variant of uncertain significance (VUS) or gene of uncertain significance (GUS); 23% had no variants reported. There was a significant difference in the average number of body systems affected among these groups (pathogenic 5.89, VUS 6.0, GUS 6.12, and no variant 4.6; P < 0.00001). Representative cases highlight four ways in which CES is changing clinical pediatric practice., Conclusions: Patients with identified variants are enriched for multiple organ system involvement. Furthermore, our phenotyping provides broad insights into which patients are most likely to benefit from genetics referral and CES and how those results can help guide clinical practice more generally.

Purpose: CHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome., Methods: We performed whole-exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome., Results: Pathogenic variants in CHD7 were present in 15 of 28 individuals (53.6%), whereas 4 (14.3%) individuals had pathogenic variants in other genes (RERE, KMT2D, EP300, or PUF60). A variant of uncertain clinical significance in KDM6A was identified in one (3.5%) individual. The remaining eight (28.6%) individuals were not found to have pathogenic variants by WES., Conclusion: These results demonstrate that the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes. Additionally, they implicate a shared molecular pathology that disrupts epigenetic regulation of multiple-organ development.

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype-phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7., (© 2018 Wiley Periodicals, Inc.)

We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated., (Copyright © 2017. Published by Elsevier Inc.)

Copy number variation (CNV) in the long arm of chromosome 2 has been implicated in developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), congenital anomalies, and psychiatric disorders. Here we describe 14 new subjects with recurrent deletions and duplications of chromosome 2q11.2, 2q13, and 2q11.2-2q13. Though diverse phenotypes are associated with these CNVs, some common features have emerged. Subjects with 2q11.2 deletions often exhibit DD, speech delay, and attention deficit hyperactivity disorder (ADHD), whereas those with 2q11.2 duplications have DD, gastroesophageal reflux, and short stature. Congenital heart defects (CHDs), hypotonia, dysmorphic features, and abnormal head size are common in those with 2q13 deletions. In the 2q13 duplication cohort, we report dysmorphic features, DD, and abnormal head size. Two individuals with large duplications spanning 2q11.2-2q13 have dysmorphic features, hypotonia, and DD. This compilation of clinical features associated with 2q CNVs provides information that will be useful for healthcare providers and for families of affected children. However, the reduced penetrance and variable expressivity associated with these recurrent CNVs makes genetic counseling and prediction of outcomes challenging. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Introduction: Differences in the prevalence of psychiatric conditions such as psychosis as well as patterns of comorbidity for psychosis have been reported between racial and ethnic groups. It is unclear whether those differences are consistent for comorbid psychosis Methods: Self-reported diagnostic data from American adults ages 18-99 participating in the Collaborative Psychiatric Epidemiology Surveys (CPES) (N ~ 11,844) were used to test the association between four racial and ethnic group categories (White, Asian, Hispanic, Black) and comorbid psychosis. Comorbid psychosis was measured as a 4-level categorical variable (No mental illness nor psychosis, Mental Illness, Psychosis only, comorbid psychosis (i.e., Psychosis + Mental Illness). Chi-square tests were used to determine significant differences in the prevalence of comorbid psychosis by race and ethnicity. A multinomial logistic regression was used to test the association between racial and ethnic classifications and comorbid psychosis after adjusting for common demographic characteristics (i.e., education, sex, income, and age). Results: Relative to White participants, Hispanic and Asian participants were less likely to be affected with comorbid psychosis. (Adjusted Odds Ratio, AORAsian = 0.32, CI = 0.22 - 0.47, p <0.0001, AORHispanic = 0.66, CI = 0.48 - 0.92, p = 0.012). Relative to White participants there was not significant association for comorbid psychosis in Black participants (AORBlack = 0.91, CI = 0.70 - 1.20, p = 0.52) In contrast Hispanic and Black participants were more likely to report psychosis alone (AORHispanic = 1.94, CI = 1.27-2.98, p = 0.002, AORBlack = 1.86, 1.24-2.82, p = 0.003) compared to White participants. Conclusion: There were different patterns of associations by race and ethnicity for psychosis and comorbid psychosis. The lower prevalence of comorbid psychosis in non-White groups may be due to underdiagnosis or underreporting of other mental disorders. [ABSTRACT FROM AUTHOR]

Recurrent 2q13 deletion syndrome is associated with incompletely penetrant severe cardiac defects and craniofacial anomalies. We used an atypical, overlapping 1.34 Mb 2q13 deletion in a patient with pathogenically similar congenital heart defects (CHD) to narrow the putative critical region for CHD to 474 kb containing six genes. To determine which of these genes is responsible for severe cardiac and craniofacial defects noted in the patients with the deletions, we used zebrafish morpholino knockdown to test the function of each orthologue during zebrafish development. Morpholino-antisense-mediated depletion of fibulin-7B, a zebrafish orthologue of fibulin-7 (FBLN7), resulted in cardiac hypoplasia, deficient craniofacial cartilage deposition and impaired branchial arch development. TMEM87B depletion likewise resulted in cardiac hypoplasia but with preserved branchial arch development. Depletion of both fibulin-7B and TMEM87B resulted in more severe defects of cardiac development, suggesting that their concurrent loss may enhance the risk of a severe cardiac defect. We postulate that heterozygous loss of FBLN7 and TMEM87B account for some of the clinical features, including cardiac defects and craniofacial abnormalities associated with 2q13 deletion syndrome., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Sonography is usually requested to evaluate palpable pediatric breast lumps, and solid masses are almost always fibroadenomas. Lack of familiarity with the findings of fibroadenomas can lead to diagnostic uncertainty and sometimes unnecessary biopsy and excision. We sought to review the spectrum of sonographic findings in our cases of pathology proven pediatric fibroadenomas., Objective: The purpose of this retrospective study was to describe the sonographic appearances of pathologically proven pediatric breast fibroadenomas., Materials and Methods: A query of the Department of Radiology database at our institution was performed for all patients younger than 19 years who underwent breast US from January 2001 to June 2009. A total of 332 patients were identified: 282 girls (85%) and 50 boys (15%). Ninety-one girls and no boys had a solid breast mass based on US findings. Forty-three children had a total of 49 pathologically proven breast masses with the diagnoses of fibroadenoma (44), hamartoma (1), non-Hodgkin lymphoma (1), tubular adenoma (1), pseudoangiomatous stromal hyperplasia (1) and lactation changes (1). Reviews of medical records, histological results and sonographic examinations of all pathology-proven fibroadenomas were performed. US findings were characterized according to location, multiplicity, size, shape, echogenicity and homogeneity, definition of margins, posterior acoustic features and Doppler vascularity., Results: The vast majority of solid breast masses in girls are histologically benign. Fibroadenomas accounted for 91% of the pathologically proven solid breast masses. Common findings on US imaging are an oval shape, hypoechoic echo pattern, posterior acoustic enhancement and internal Doppler signal. Lobulations were found in 57% of the masses. Less common findings are absent internal vascular flow and complex echo pattern, while isoechoic echo pattern, posterior shadowing and angular margins are rare or unusual., Conclusion: Fibroadenomas represent the most common solid mass in the breasts of girls. Sonographic appearances are usually characteristic and do not significantly differ from those found in adults. The radiologist must be aware of common and uncommon sonographic appearances of fibroadenomas in the pediatric age group and should be cautious when recommending histological confirmation based on imaging findings, as breast malignancy is extremely rare.

Introduction and purpose: Gaucher's Disease (GD), a rare genetic disorder, is a difficult challenge in genetic and metabolic disorders. The aim of this review is to provide an exploration of GD, spanning its pathophysiology to the latest advancements in diagnostic and therapeutic innovations. In this review we aimed to underscore the challenges it presents and the ongoing efforts to overcome them. State of knowledge: GD, characterized by the accumulation of glucocerebroside, involves molecular, cellular, and systemic dysfunctions. At the molecular level, mutations in the GBA gene give rise to diverse manifestations, influencing disease severity. Cellular disruptions lead to lysosomal dysfunction, altered calcium homeostasis, and chronic inflammation, impacting various organ systems. Diagnostic approaches involve biomarkers, genetic testing, and imaging studies, each playing a crucial role in confirming the disease type and assessing its grade. Summary: Management and treatment strategies for GD have evolved, with enzyme replacement therapy and substrate reduction therapy serving as the basics. However, challenges persist, including limited efficacy in treating neurological symptoms and the high cost of treatments. The review highlights ongoing research and future perspectives in GD therapy. [ABSTRACT FROM AUTHOR]

Background: Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. Methods: We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. Findings: A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10−31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. Conclusions: Our findings highlight the importance of causal genes for VV and provide new directions for treatment. Author summary: In this study, whole-exome sequencing data from the UK Biobank were used to explore the effect of genetic variants on varicose veins (VV) and search for new VV-related genes. In contrast to traditional association studies, large-scale whole-exome sequencing analysis is more capable of identifying rare genetic variants (MAF < 1%) in diseases. The current study identified 34 VV-associated common variant genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations were validated in FinnGen. In addition to replicating several genes reported in previous genome-wide association studies, we identified 17 novel genes that may be associated with VV. Through subsequent phenome-wide association analyses of identified genes, we found that these genes are also strongly associated with body size, inflammation, and pulmonary function. These findings contribute to understanding the underlying mechanisms of pathogenesis and developing novel therapeutic strategies for VV. [ABSTRACT FROM AUTHOR]

Background: Waardenburg syndrome (WS) is a rare genetic disorder mainly characterized by hearing loss and pigmentary abnormalities. Currently, seven causative genes have been identified for WS, but clinical genetic testing results show that 38.9% of WS patients remain molecularly unexplained. In this study, we performed multi-data integration analysis through protein-protein interaction and phenotype-similarity to comprehensively decipher the potential causative factors of undiagnosed WS. In addition, we explored the association between genotypes and phenotypes in WS with the manually collected 443 cases from published literature. Results: We predicted two possible WS pathogenic genes (KIT, CHD7) through multi-data integration analysis, which were further supported by gene expression profiles in single cells and phenotypes in gene knockout mouse. We also predicted twenty, seven, and five potential WS pathogenic variations in gene PAX3, MITF, and SOX10, respectively. Genotype-phenotype association analysis showed that white forelock and telecanthus were dominantly present in patients with PAX3 variants; skin freckles and premature graying of hair were more frequently observed in cases with MITF variants; while aganglionic megacolon and constipation occurred more often in those with SOX10 variants. Patients with variations of PAX3 and MITF were more likely to have synophrys and broad nasal root. Iris pigmentary abnormality was more common in patients with variations of PAX3 and SOX10. Moreover, we found that patients with variants of SOX10 had a higher risk of suffering from auditory system diseases and nervous system diseases, which were closely associated with the high expression abundance of SOX10 in ear tissues and brain tissues. Conclusions: Our study provides new insights into the potential causative factors of WS and an alternative way to explore clinically undiagnosed cases, which will promote clinical diagnosis and genetic counseling. However, the two potential disease-causing genes (KIT, CHD7) and 32 potential pathogenic variants (PAX3: 20, MITF: 7, SOX10: 5) predicted by multi-data integration in this study are all computational predictions and need to be further verified through experiments in follow-up research. [ABSTRACT FROM AUTHOR]

This paper examines the proportion of males who have sexually coerced someone. In this survey, we extracted data from 60 published papers with a cumulative sample size of 26,717 men. From these data, we calculated the weighted mean proportion of males who reported having sexually coerced someone. While we did find studies that contained non-heterosexual data, the dearth of such data reveals the need for more research on male non-heterosexual coercion. Our results show that 29.8% of heterosexual males have sexually coerced a woman some time in their lives, which is consistent with previous estimates of male heterosexual coercion. We also found that 27.3% of non-heterosexual males have coerced someone, a number close to the perpetration rate for non-heterosexual females. When compared with previously reported rates of heterosexual female perpetration of sexual coercion, the heterosexual male rate of 29.8% will be shown to be consistent with known rape data, such as results from the Online College Social Life Survey, which show that 85–90% of raped men are raped by women. The concurrence with previous research on American and Canadian college students suggests that the proportion of sexually coercive heterosexual men is the same for these countries as the overall rate internationally. [ABSTRACT FROM AUTHOR]

AUTS2 haploinsufficiency causes a neurodevelopmental disorder known as AUTS2, which is characterized by global developmental delay, intellectual disability, autistic features, congenital brain anomalies, and other malformations. In this study, we report a case of AUST2 syndrome and describe the clinical manifestations and genetic etiology as well as provide a review of the literature. A 5-year-old girl presented with neurodevelopmental manifestations, skeletal features and dysmorphic features. Whole exome sequencing was carried out for the proband. A novel, heterozygous variant (c.1606C>T) in AUTS2 gene was identified. Sanger sequencing confirmed the presence of this variant in the affected girl; however, it was not detected in all family members. The identified variant is predicted to cause premature termination of the corresponding AUTS2 protein (p.Gln536*), which will likely lack the C-terminal domain of the protein. This study revealed a novel de novo loss-of-function variant in the AUTS2 gene and further expanded the phenotypic and genetic spectra of the AUTS2 syndrome. Moreover, this result might be helpful in genetic counseling for families with clinical phenotypes related to this syndrome. Further functional experiments are required to validate the impact of the identified variant. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by mutations in the GLA gene encoding alpha-galactosidase A (α-Gal). Loss of α-Gal activity leads to progressive lysosomal accumulation of α-Gal substrate, predominately globotriaosylceramide (Gb3) and its deacylated derivative globotriaosylsphingosine (lyso‐Gb3). FD manifestations include early onset neuropathic pain, gastrointestinal symptoms, and later onset life-threatening renal, cardiovascular and cerebrovascular disorders. Current treatments can preserve kidney function but are not very effective in preventing progression of cardiovascular pathology which remains the most common cause of premature death in FD patients. There is a significant need for a translational model that could be used for testing cardiac efficacy of new drugs. Two mouse models of FD have been developed. The α-Gal A-knockout (GlaKO) model is characterized by progressive tissue accumulation of Gb3 and lyso-Gb3 but does not develop any Fabry pathology besides mild peripheral neuropathy. Reports of minor cardiac function abnormalities in GlaKO model are inconsistent between different studies. Recently, G3Stg/GlaKO was generated by crossbreeding GlaKO with transgenic mice expressing human Gb3 synthase. G3Stg/GlaKO demonstrate higher tissue substrate accumulation and develop cellular and tissue pathologies. Functional renal pathology analogous to that found in early stages of FD has also been described in this model. The objective of this study is to characterize cardiac phenotype in GlaKO and G3Stg/GlaKO mice using echocardiography. Longitudinal assessments of cardiac wall thickness, mass and function were performed in GlaKO and wild-type (WT) littermate controls from 5–13 months of age. G3Stg/GlaKO and WT mice were assessed between 27–28 weeks of age due to their shortened lifespan. Several cardiomyopathy characteristics of early Fabry pathology were found in GlaKO mice, including mild cardiomegaly [up-to-25% increase in left ventricular (LV mass)] with no significant LV wall thickening. The LV internal diameter was significantly wider (up-to-24% increase at 9-months), when compared to the age-matched WT. In addition, there were significant increases in the end-systolic, end-diastolic volumes and stroke volume, suggesting volume overload. Significant reduction in Global longitudinal strain (GLS) measuring local myofiber contractility of the LV was also detected at 13-months. Similar GLS reduction was also reported in FD patients. Parameters such as ejection fraction, fractional shortening and cardiac output were either only slightly affected or were not different from controls. On the other hand, some of the cardiac findings in G3Stg/GlaKO mice were inconsistent with Fabry cardiomyopathy seen in FD patients. This could be potentially an artifact of the Gb3 synthase overexpression under a strong ubiquitous promoter. In conclusion, GlaKO mouse model presents mild cardiomegaly, mild cardiac dysfunction, but significant cardiac volume overload and functional changes in GLS that can be used as translational biomarkers to determine cardiac efficacy of novel treatment modalities. The level of tissue Gb3 accumulation in G3Stg/GlaKO mouse more closely recapitulates the level of substrate accumulation in FD patients and may provide better translatability of the efficacy of new therapeutics in clearing pathological substrates from cardiac tissues. But interpretation of the effect of treatment on cardiac structure and function in this model should be approached with caution. [ABSTRACT FROM AUTHOR]

Purpose: Physical dating aggression is prevalent within young adulthood, yet little is known about within-relationship effects of physical dating aggression on psychosocial adjustment. The present study uses an intensive longitudinal design to capture proximal changes (i.e., one month later, and across 6 months) in psychosocial adjustment following physical dating aggression. Methods: Between 2014 and 2016, data was collected in six monthly waves from 120 participants ages 18–25 (50% female, M age Wave 1 = 22.44; 10% African American, 17.5% Hispanic. 62.5% Caucasian). Results: Both immediate changes in the level of psychosocial adjustment and the growth trajectory of psychosocial adjustment were examined. Wave 1 physical dating aggression was associated with immediate changes in internalizing and trauma symptoms. Further, Wave 1 physical dating aggression predicted increased growth in both externalizing and internalizing symptoms. Conclusions: Findings highlight that psychological consequences of physical dating aggression may emerge quickly, with implications for potential increased risk for subsequent involvement in physical dating aggression. [ABSTRACT FROM AUTHOR]

The transcriptional regulation of genes is a complex process, particularly for genes exhibiting a tissue-specific pattern of expression. We studied 28 genes that are expressed primarily in endothelial cells, another 28 genes that are expressed highly, but not exclusively, in cultured endothelial cells, and three control sets, consisting of genes not expressed in endothelium, genes expressed in neural tissues and housekeeping genes. For each gene, we identified conserved non-coding sequences (CNSs) of lengths 50 to >1000 nucleotides, located within the upstream intergenic region (from 500 to as far as 200 000 nucleotides upstream from the transcription start) or within the first intron. As a functional test, we assayed the CNSs from the set of endothelial cell-specific genes (EC-CNSs) for DNase hypersensitivity. Among 262 distant EC-CNSs, 33% are hypersensitive (HS) in endothelial cells, whereas only 16% are HS in control fibroblasts. A search for short sequence patterns revealed a number of motifs which are over-represented in EC-CNSs relative to CNSs from the control gene sets. In particular, the motif SAGGAAR is strongly and consistently over-represented among EC-CNSs, and is more over-represented in HS CNSs than in non-HS CNSs. CNSs which contain this motif are no closer to the promoter than an average CNS. This motif contains the core element of binding sites from the Ets family of transcription factors. Thus, one or several factors from this family may play a key role in the regulation of endothelial gene expression.

A major goal in genomics is to understand how genes are regulated in different tissues, stages of development, diseases, and species. Mapping DNase I hypersensitive (HS) sites within nuclear chromatin is a powerful and well-established method of identifying many different types of regulatory elements, but in the past it has been limited to analysis of single loci. We have recently described a protocol to generate a genome-wide library of DNase HS sites. Here, we report high-throughput analysis, using massively parallel signature sequencing (MPSS), of 230,000 tags from a DNase library generated from quiescent human CD4+ T cells. Of the tags that uniquely map to the genome, we identified 14,190 clusters of sequences that group within close proximity to each other. By using a real-time PCR strategy, we determined that the majority of these clusters represent valid DNase HS sites. Approximately 80% of these DNase HS sites uniquely map within one or more annotated regions of the genome believed to contain regulatory elements, including regions 2 kb upstream of genes, CpG islands, and highly conserved sequences. Most DNase HS sites identified in CD4+ T cells are also HS in CD8+ T cells, B cells, hepatocytes, human umbilical vein endothelial cells (HUVECs), and HeLa cells. However, approximately 10% of the DNase HS sites are lymphocyte specific, indicating that this procedure can identify gene regulatory elements that control cell type specificity. This strategy, which can be applied to any cell line or tissue, will enable a better understanding of how chromatin structure dictates cell function and fate.

Mutations in LMAN1 (also called ERGIC-53) result in combined deficiency of factor V and factor VIII (F5F8D), an autosomal recessive bleeding disorder characterized by coordinate reduction of both clotting proteins. LMAN1 is a mannose-binding type 1 transmembrane protein localized to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC; refs. 2,3), suggesting that F5F8D could result from a defect in secretion of factor V and factor VIII (ref. 4). Correctly folded proteins destined for secretion are packaged in the ER into COPII-coated vesicles, which subsequently fuse to form the ERGIC. Secretion of certain abundant proteins suggests a default pathway requiring no export signals (bulk flow; refs. 6,7). An alternative mechanism involves selective packaging of secreted proteins with the help of specific cargo receptors. The latter model would be consistent with mutations in LMAN1 causing a selective block to export of factor V and factor VIII. But approximately 30% of individuals with F5F8D have normal levels of LMAN1, suggesting that mutations in another gene may also be associated with F5F8D. Here we show that inactivating mutations in MCFD2 cause F5F8D with a phenotype indistinguishable from that caused by mutations in LMAN1. MCFD2 is localized to the ERGIC through a direct, calcium-dependent interaction with LMAN1. These findings suggest that the MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.

Heterochromatin protein 1 (HP1), first discovered in Drosophila melanogaster, is a highly conserved chromosomal protein implicated in both heterochromatin formation and gene silencing. We report here characterization of an HP1-interacting protein, heterochromatin protein 2 (HP2), which codistributes with HP1 in the pericentric heterochromatin. HP2 is a large protein with two major isoforms of approximately 356 and 176 kDa. The smaller isoform is produced from an alternative splicing pattern in which two exons are skipped. Both isoforms contain the domain that interacts with HP1; the larger isoform contains two AT-hook motifs. Mutations recovered in HP2 act as dominant suppressors of position effect variegation, confirming a role in heterochromatin spreading and gene silencing.

The issue of gaining prescription privileges and its potential impact on the field of clinical psychology has special relevance for graduate students. This study was designed to investigate clinical graduate students' attitudes toward prescription authority, identify salient variables that contribute to these attitudes, and ascertain preferred models of training. Only 42.5% of respondents personally desired to obtain prescription privilege, although 61.8% of respondents favored efforts of the American Psychological Association to acquire prescription authority. Proponents and opponents were compared on their ratings of positive and negative aspects of the debate. There was strong agreement that the training should not be predoctoral and that it should lead to board certification. The strongest predictors of graduate students' attitudes were concerns about fundamental change to the field, malpractice premiums, and whether they considered it a logical extension of the field. This study provides a framework for understanding important factors influencing the decision-making process among clinical psychology graduate students., (Copyright 2002 Wiley Periodicals, Inc.)

We tested the hypothesis that race may influence clinical presentation and symptomatology in combat veterans with posttraumatic stress disorder (PTSD). African-American and Caucasian veterans were administered the Psychotic Screen Module of the Structured Clinical Interview for DSM, Minnesota Multiphasic Personality Inventory-2 (MMPI-2), and other psychometric measures at a Veterans Affairs outpatient PTSD clinic. Subjects were consecutive referrals who were not matched for level of combat trauma or preexisting trauma; however, there were no group differences in other relevant demographic or diagnostic variables. Significant racial differences, with modest effect sizes, were found on clinician ratings of psychotic symptoms, MMPI-2 scale 6 ("paranoia"), and a measure of dissociation. No significant differences were found for the MMPI-2 scale 8 ("schizophrenia"), or on measures that might suggest comorbid depression or anxiety. African-Americans with PTSD endorsed more items suggesting positive symptoms of psychosis, without higher rates of primary psychosis, depression, or anxiety than Caucasians., (Copyright 2002 Wiley-Liss, Inc.)

This study examined the relationship between homophobia (defined as self-reported negative affect, avoidance, and aggression toward homosexuals) and homosexual aggression. Self-identified heterosexual college men were assigned to homophobic (n = 26) and nonhomophobic (n = 26) groups on the basis of their scores on the Homophobia Scale (HS; L. W. Wright, H. E. Adams, & J. A. Bernat, 1999). Physical aggression was examined by having participants administer shocks to a fictitious opponent during a competitive reaction time (RT) task under the impression that the study was examining the relationship between sexually explicit material and RT. Participants were exposed to a male homosexual erotic videotape, their affective reactions were assessed, and they then competed in the RT task against either a heterosexual or a homosexual opponent. The homophobic group reported significantly more negative affect, anxiety, and anger-hostility after watching the homosexual erotic videotape than did the nonhomophobic group. Additionally, the homophobic group was significantly more aggressive toward the homosexual opponent, but the groups did not differ in aggression toward the heterosexual opponent.

Self-identified sexually aggressive (SA) and nonaggressive (NA) college men listened to audiotape analogues of consensual sexual intercourse and acquaintance rape. Phallometric and decision-latency methodology was used to examine sexual arousal and decisions to stop sexual advances in each scenario. Both groups showed increases in penile response to the consensual scenario. Consistent with the inhibition model of sexual aggression, the SA group showed greater sexual arousal and failed to inhibit responding when force was introduced in the rape, whereas the NA group exhibited less arousal and greater inhibition to force. The SA group allowed the rape to continue significantly longer than the NA group. These effects were greatly magnified in SA men who endorsed high calloused sexual beliefs, implying that a cognitive set that justifies sexual aggression and lacks victim empathy may disinhibit sexual arousal and potentiate coercive decision making.

This study used experimental methodology to investigate the differential impact of various levels of sexual victimization on women's perceptions of risk and evaluative judgments of sexual assault within a dating interaction. Single- and multiple-incident victims were compared with nonvictims. Results supported the hypothesis that revictimized women would exhibit longer latencies than either single-incident victims or nonvictims in signaling that an audiotaped date rape should be halted. Revictimized women with greater posttraumatic stress disorder (PTSD) symptoms, arousal symptoms in particular, exhibited latencies similar to those of nonvictims, whereas revictimized women with lower levels of PTSD symptoms had significantly longer latencies. Dissociative symptoms were not related to latency. These findings suggest that PTSD-related arousal symptoms may serve a buffering effect, increasing sensitivity to threat cues that portend a sexually coercive interaction.

This study compared men with and without a history of coercive sexual behavior on their judgments of how far a man should go in using coercion in an audiotaped date rape simulation. Calloused sexual beliefs (CSB) and a "token resistance" manipulation were expected to differentially interact with coercion history. Results showed no effect for "token resistance." Calloused sexual beliefs interacted with coercion group, such that sexually coercive men high in CSB took significantly longer to stop the date rape interaction than coercive men low in CSB, who did not differ from noncoercive men. These findings support a model of sexual coercion in which a cognitive set consisting of rape-supportive beliefs may serve as a disinhibitor of behavior.

This study investigated lifetime prevalence of traumatic events and posttraumatic stress disorder (PTSD) symptoms among 937 college students. Participants rated their lifetime experiences of traumatic events and, in response to their "most stressful" event, completed measures of objective stressor dimensions, PTSD, and peritraumatic reactions. Approximately 67% of respondents reported at least one traumatic event. An estimated 4% of the full sample (12% of traumatized individuals) met PTSD criteria within the past week. After controlling for vulnerability factors and objective characteristics, peritraumatic reactions remained strongly predictive of PTSD symptoms. Results are discussed with respect to immediate reactions to traumatic events as potential precursors of PTSD symptomatology.

Background: Despite the fact that studies indicate that earthquake trauma is associated with numerous psychological consequences, the mediating mechanisms leading to these outcomes have not been well-studied. Therefore, this study investigates the relationship between trauma exposure with substance use tendency, depression, and suicidal thoughts, with the mediating role of peritraumatic dissociation and experiential avoidance. Methods: The descriptive-correlational approach was employed in this study. The participants were people who had experienced the Kermanshah earthquake in 2017. A total of 324 people were selected by convenient sampling method. The Traumatic Exposure Severity Scale, the Peritraumatic Dissociative Experiences Questionnaire, the Acceptance and Action Questionnaire, the Iranian Addiction Potential Scale, Beck's Depression Inventory [BDI-II], and Beck's Suicidal Thoughts Scale were used to collect data. The gathered data was analyzed‌ using structural equation modeling in ‌SPSS Ver. 24 and LISREL Ver. 24. Results: The study findings indicated that the intensity of the trauma exposure is directly and significantly associated with depression symptoms, peritraumatic dissociation, and experiential avoidance. The severity of exposure to trauma had a significant indirect effect on the tendency to use substances through experiential avoidance. This is while the severity of the trauma experience did not directly correlate with substance use and suicidal thoughts. In addition, peritraumatic dissociation did not act as a mediator in the relationship between the severity of trauma exposure with substance use, depression, and suicidal thoughts. Conclusions: The severity of exposure to the earthquake was associated with symptoms of depression and these findings indicate the importance of experiential avoidance in predicting the tendency to use drugs. Hence, it is essential to design and implement psychological interventions that target experiential avoidance to prevent drug use tendencies and to establish policies that lower depression symptoms following natural disasters. [ABSTRACT FROM AUTHOR]

To investigate the incidence of pathogenic recurrent CNVs in fetuses with different referral indications and review the intrauterine phenotypic features of each CNV. A total of 7,078 amniotic fluid samples were collected for chromosome microarray analysis (CMA) and cases carrying pathogenic recurrent CNVs were further studied. The highest incidence of pathogenic recurrent CNVs was 2.25 % in fetal ultrasound anomalies (FUA) group. Moreover, regardless of other indications, pregnant women with advanced maternal age have a lower incidence compared with whom less than 35 years old (p<0.05). In total 1.17 % (83/7,078) samples carried pathogenic recurrent CNVs: 20 cases with 22q11.2 recurrent region (12 microdeletion and eight microduplication), 11 with 1q21.1 (five microdeletion and six microduplication) and 16p13.11 (four microdeletion and seven microduplication), 10 with 15q11.2 recurrent microdeletion, seven with Xp22.31 recurrent microdeletion and 16p11.2 (three microdeletion and four microduplication), four with 7q11.23 (two microdeletion and two microduplication), three with 17p11.2 (three microdeletion), 17p12 (two microdeletion and one microduplication) and 17q12 (two microdeletion and one microduplication). The rest ones were rare in this study. Pathogenic recurrent CNVs are more likely to be identified in FUA group. Pregnant women with advanced maternal age have a lower incidence of pathogenic recurrent CNVs. The profile of pathogenic recurrent CNVs between prenatal and postnatal is different, especially in 22q11.2, 1q21.1, 15q13.3 recurrent region and 15q11.2 deletion. [ABSTRACT FROM AUTHOR]

Introduction: The complex structure of the chromosome 2q12.3-q13 region provides a high chance of recombination events between various low copy repeats (LCRs). Copy number variants (CNV) in this region are present in both healthy populations and individuals affected with developmental delay, autism and congenital anomalies. Variable expressivity, reduced penetrance and limited characterization of the affected genes have complicated the classification of the CNVs clinical significance., Methods: Chromosomal microarray analysis data were reviewed for 10 298 patients with neurodevelopmental disorders referred to the UPMC Medical Genetics and Genomics Laboratories. A genotype-phenotype correlation was performed among the patients harboring the 2q12.3-q13 CNVs with overlapping genomic intervals., Results: We identified 17 (1 in ~600) individuals with rare CNVs in the 2q12.3-q13 region, including nine patients with deletions, seven individuals with duplications and one patient who had both a deletion and a duplication. Likely pathogenic CNVs with the breakpoints between LCRs encompassing the potential dosage-sensitive genes BCL2L11, BUB1, FBLN7 and TMEM87B were the most common. CNVs were also observed between LCRs surrounding the RANBP2 and LIMS1 genes., Conclusion: Our study provides evidence for pathogenic CNV hotspots within the chromosome 2q12.3-q13 region. We suggest CNV classification based on the affected interval and the involvement of potential dosage-sensitive genes in these patients., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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The current study explored a form of femmephobia (specifically, negative attitudes toward femininity in men) as a predictor of anti-gay behaviors among a sample of heterosexual men (N = 417). Additional predictor variables included hierarchical worldviews (i.e., social dominance orientation, right-wing authoritarianism, narcissism) and prejudicial attitudes (i.e., old-fashioned and modern homonegativity). Femmephobia emerged as a robust predictor, accounting for 23% of the variance in anti-gay behavior, surpassing the explanatory power (15%) of all other considered variables combined. Moreover, social dominance only predicted anti-gay behavior when femmephobia levels were high. Future research on discrimination and violence related to sexual identity and gender expression should incorporate femmephobia as a key predictive factor. [ABSTRACT FROM AUTHOR]

Early life adversity has long been associated with the onset and course of criminal behavior and juvenile justice involvement. Nevertheless, there is a paucity of research on the differential experiences of early life trauma and trauma symptomology among justice involved youth of color who are ubiquitously overrepresented in the juvenile justice system (JJS). Conventional trauma instruments used in the JJS may yield limited cultural relevance or applicability to racially minoritized justice involved youth as they rarely capture concepts of race-based trauma. While research has explored the relative effects of racial trauma above and beyond other traumatic experiences among minoritized youth in the JJS, differential trauma experiences and differential effects between trauma and delinquency among racial groups have not been extensively explored. Conducting multivariate analysis of variance with appropriate post hoc tests and bivariate correlations, the results revealed significant mean differences between racial groups on experiences of early life trauma via conventional trauma instruments; white youth reported higher rates of trauma events including cumulative trauma, relative to black and Hispanic youth, but had similar rates of trauma symptoms relative to black youth. Furthermore, while there were no racial group differences on reports of delinquency, there were vastly different trauma-based risk correlates by racial group; white youth had several trauma indicators associated with delinquency, whereas black and Hispanic youth had no associations. Results suggest conventional trauma instruments have limited cultural and racial relevancy for minoritized justice involved youth. Implications are identified for intersectional youth participatory action approaches to instrument development centered on discovering raced-based traumatic stress among racially minoritized justice involved youth. [ABSTRACT FROM AUTHOR]

Brain development requires a delicate balance between self-renewal and differentiation in neural stem cells (NSC), which rely on the precise regulation of gene expression. Ten-eleven translocation 2 (TET2) modulates gene expression by the hydroxymethylation of 5-methylcytosine in DNA as an important epigenetic factor and participates in the neuronal differentiation. Yet, the regulation of TET2 in the process of neuronal differentiation remains unknown. Here, the protein level of TET2 was reduced by the ubiquitin-proteasome pathway during NSC differentiation, in contrast to mRNA level. We identified that TET2 physically interacts with the core subunits of the glucose-induced degradation-deficient (GID) ubiquitin ligase complex, an evolutionarily conserved ubiquitin ligase complex and is ubiquitinated by itself. The protein levels of GID complex subunits increased reciprocally with TET2 level upon NSC differentiation. The silencing of the core subunits of the GID complex, including WDR26 and ARMC8, attenuated the ubiquitination and degradation of TET2, increased the global 5-hydroxymethylcytosine levels, and promoted the differentiation of the NSC. TET2 level increased in the brain of the Wdr26+/− mice. Our results illustrated that the GID complex negatively regulates TET2 protein stability, further modulates NSC differentiation, and represents a novel regulatory mechanism involved in brain development. [ABSTRACT FROM AUTHOR]

Hereditary syndromes, such as familial adenomatous polyposis (FAP), MUTYH polyposis or Lynch syndrome, are particularly predisposing to the development of colorectal cancer. These situations have necessitated the development of adapted prevention strategies based largely on reinforced endoscopic surveillance and the search for complementary prevention strategies. This is the case for chemoprevention, which is the long-term administration of chemical agents limiting carcinogenesis, used as primary or secondary prophylaxis. The aim of this review is to present the available literature and the latest advances in chemoprevention in patients with FAP or MUTYH and other polyposis as well as in patients with Lynch syndrome. The main conclusions of the few available guidelines in these situations are also discussed. [ABSTRACT FROM AUTHOR]