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A new structure to design observers for linear systems is presented in this work. The key step is the construction of two layers where the first consists of multiple observers and the second connects them providing the weighted estimation state. The main difficulty is to find a new feedback which is responsible for control weights. To define observation law, we rely on multi observers from the first layer. The proposed structure significantly improves the transient characteristics of the observation process, which is shown in illustrative examples.

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.)

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.

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.