Mutations in TRAPPC11 are associated with a congenital disorder of glycosylation.

Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex. TRAPPIII is implicated in the anterograde transport from the ER to the ERGIC as well as in the vesicle export from the GA. This report expands the spectrum of genetic alterations associated with CDG, providing new insights for the diagnosis and the understanding of the physiopathological mechanisms underlying glycosylation disorders

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Publisher Copyright: © 2022 The AuthorsBackground: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268). Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10−6) in older children and had methylation differences in the same direction. Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.Peer reviewe

Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

This is the final version. Available from BMC via the DOI in this record. Individual cohort-level data can be obtained from the respective cohort (see Additional file 1: Table S1 and Additional file 2 for cohort details).BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.Wellcome TrustBiotechnology and Biological Sciences Research Council (BBSRC)Biotechnology and Biological Sciences Research Council (BBSRC)European Union’s Horizon 2020Economic and Social Research Council (ESRC)Medical Research Council (MRC)Medical Research Council (MRC)European UnionSwedish foundation for strategic research (SSF)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Environmental Protection Agency (EPA)National Cancer Institute Cancer CenterNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Environmental Protection Agency (EPA)Environmental Protection Agency (EPA)European UnionEuropean UnionEuropean UnionEuropean UnionEuropean Union’s Horizon 2020European Research Council (ERC)German Ministry of Education and ResearchNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Autism SpeaksNational Institutes of Health (NIH)National Institutes of Health (NIH)European UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean Research Council (ERC)Flemisch Scientific Research CouncilFlemisch Scientific Research CouncilFlemisch Scientific Research CouncilEuropean UnionFonds de recherche du Québec - Santé (FRQS)Canadian Institute of Health Research (CIHR)Canadian Institute of Health Research (CIHR)Netherlands Organisation for Scientific Research (NWO)National Institute of Child and Human DevelopmentEuropean Union’s Horizon 2020European Union’s Horizon 2020European Union’s Horizon 2020ZonMwZonMwMedical Research Council Integrative Epidemiology Unit (University of Bristol)Netherlands Heart FoundationNetherlands Heart FoundationNetherlands Organisation for Scientific Research (NWO)European UnionNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Spanish Ministry of ScienceNational Institute for Health and Care Research (NIHR)Wellcome TrustNorwegian Ministry of Health and the Ministry of Education and ResearchNorwegian Ministry of Health and the Ministry of Education and ResearchNorwegian Ministry of Health and the Ministry of Education and ResearchLithuanian Agency for Science Innovation and TechnologySpanish Ministry of HealthSpanish Ministry of HealthSpanish Ministry of HealthSpanish Ministry of HealthSpanish Ministry of HealthInstituto de Salud Carlos IIIInstituto de Salud Carlos IIIEuropean Research Council (ERC)CDMRP/Department of DefenseNIGMSNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Asthma Campaign, UKNational Institutes of Health (NIH)Medical Research Council (MRC)National Institutes of Health (NIH)Norwegian Research CouncilNational Institute of Environmental Health SciencesResearch Council of NorwayNational Institute of Environmental Health SciencesNational Institute of Environmental Health SciencesNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of Environmental Health SciencesNational Institute of Environmental Health SciencesSwedish Research CouncilSwedish Initiative for research on Microdata in the Social And Medical Sciences (SIMSAM)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Medical Research Council Integrative Epidemiology Unit (University of Bristol)Medical Research Council Integrative Epidemiology Unit (University of Bristol)Medical Research Council Integrative Epidemiology Unit (University of Bristol)Swedish Heart-Lung FoundationUniversity of MunichFoundation for Medical Research (FRM)National Agency for ResearchNational Institute for Research in Public HealthFrench Ministry of HealthFrench Ministry of ResearchInserm Bone and Joint Diseases National Research (PRO-A) and Human Nutrition National Research ProgramsParis–Sud UniversityNestléFrench National Institute for Population Health SurveillanceFrench National Institute for Health EducationFrench Agency for Environmental Health SafetyMutuelle Générale de l’Education NationaleFrench National Agency for Food SecurityFrench-speaking association for the study of diabetes and metabolismItalian National Centre for Disease Prevention and ControlItalian Ministry of HealthGreek Ministry of HealthFlemish Government (Department of Economy, Science and Innovations, Agency for Care and Health and Department of Environment)The Research Foundation-FlandersFlemish Institute for Technological ResearchDiabète QuébecErasmus University RotterdamNetherlands Organization for Health Research and Development and the Ministry of Health, Welfare and SportErasmus MCDanish National Research FoundationDanish Regional CommitteesNovo Nordisk FoundationLundbeck FoundationHelmholtz Center for Environmental ResearchGerman Cancer Research CentreAcademy of FinlandEraNetEVOUniversity of Helsinki Research FundsSigne and Ane Gyllenberg foundationEmil Aaltonen FoundationFinnish Medical FoundationJane and Aatos Erkko FoundationJuho Vainio foundationYrjö Jahnsson foundationJalmari and Rauha Ahokas foundationPaivikki and Sakari Sohlberg FoundationSigrid Juselius FoundationSir Jules Thorn Charitable TrustSwedish Asthma and Allergy Association's Research FoundationStiftelsen Frimurare Barnhuset Stockhol

The Usefulness of Dermoscopy for the Recognition of Malignant Collision Tumors

Background: Preoperative diagnosis of malignant collision tumors (MCT) is extremely difficult. The value of dermoscopy to improve the correct detection of these tumors has not been previously studied. This study aims to evaluate the diagnostic accuracy of MCT with and without dermoscopy and to describe the dermoscopic features of a large series of MCT. Methods: Dermoscopic images of 161 MCT were evaluated. Clinical and dermoscopic images of histopathologically proven MCT intermingled with other tumors were randomly presented to clinicians with different levels of experience, blinded to the diagnosis and objective of the study. The clinical and dermoscopic diagnostic accuracies were measured separately. Results: A total of 161 histopathologically proven cases of MCT were collected. The most frequent MCT was basal cell carcinoma-seborrheic keratosis collision tumor (CT; 37.9%), followed by basal cell carcinoma-melanocytic nevus CT (19.9%), and melanoma-seborrheic keratosis CT (6.8%). Diagnostic accuracy among experts on dermoscopy was 71.4%. The study included 119 participants. The percentage of correct diagnoses was 8% by naked eye examination and 36.4% by dermoscopy (p &lt; 0.001). The presence of the malignant component in the cases of MCT was not recognizable in 19.1% of cases by naked eye examination and in 11.8% of cases by dermoscopy (p &lt; 0.001). Conclusions: The diagnosis of MCT can be assisted and clarified by dermoscopy. However, many of these lesions manifest complex morphologies and continue to be challenging, even for experts on dermoscopy. Atypical, uncertain, or non-classifiable lesions still need a complete excision for the final diagnosis

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268). Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p \u3c 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p \u3c 1.1 × 10−6) in older children and had methylation differences in the same direction. Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits.& nbsp;Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268).& nbsp;Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 x 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 x 10-6) in older children and had methylation differences in the same direction.& nbsp;Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes