CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature.

Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features, and/or behavior abnormalities. It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency. We collected clinical and molecular data from 26 individuals carrying pathogenic variants and variants of uncertain significance (VUS) in the CUL3 gene, including 20 previously unreported cases.

Exploring nanopore direct sequencing performance of forensic STRs, SNPs, InDels, and DNA methylation markers in a single assay.

Introduction: The field of forensic DNA analysis has undergone rapid advancements in recent decades. The integration of massively parallel sequencing (MPS) has notably expanded the forensic toolkit, moving beyond identity matching to predicting phenotypic traits and biogeographical ancestry. This shift is of particular significance in cases where conventional DNA profiling fails to identify a single suspect.

A comprehensive lifestyle index and its associations with DNA methylation and type 2 diabetes among Ghanaian adults: the rodam study.

Background: A series of modifiable lifestyle factors, such as diet quality, physical activity, alcohol intake, and smoking, may drive the rising burden of type 2 diabetes (T2DM) among sub-Saharan Africans globally. It is unclear whether epigenetic changes play a mediatory role in the associations between these lifestyle factors and T2DM. We assessed the associations between a comprehensive lifestyle index, DNA methylation and T2DM among Ghanaian adults.

Molecular signatures in Mendelian neurodevelopment: a focus on ubiquitination driven DNA methylation aberrations.

Mendelian disorders, arising from pathogenic variations within single genetic loci, often manifest as neurodevelopmental disorders (NDDs), affecting a significant portion of the pediatric population worldwide. These disorders are marked by atypical brain development, intellectual disabilities, and various associated phenotypic traits. Genetic testing aids in clinical diagnoses, but inconclusive results can prolong confirmation processes.

Distinct saliva DNA methylation profiles in relation to treatment outcome in youth with posttraumatic stress disorder.

In youth with posttraumatic stress disorder (PTSD) non-response rates after treatment are often high. Epigenetic mechanisms such as DNA methylation (DNAm) have previously been linked to PTSD pathogenesis, additionally DNAm may affect response to (psychological) therapies. Besides investigating the direct link between DNAm and treatment response, it might be helpful to investigate the link between DNAm and previously associated biological mechanisms with treatment outcome.

Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype.

Blepharophimosis with intellectual disability (BIS) is a recently recognized disorder distinct from Nicolaides-Baraister syndrome that presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability. BIS is caused by pathogenic variants in SMARCA2, that encodes the catalytic subunit of the superfamily II helicase group of the BRG1 and BRM-associated factors (BAF) forming the BAF complex, a chromatin remodeling complex involved in transcriptional regulation. Individuals bearing variants within the bipartite nuclear localization (BNL) signal domain of ADNP present with the neurodevelopmental disorder known as Helsmoortel-Van Der Aa Syndrome (HVDAS).

The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes.

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm).

DNA methylation episignature and comparative epigenomic profiling for Pitt-Hopkins syndrome caused by TCF4 variants.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by pathogenic variants in TCF4, leading to intellectual disability, specific morphological features, and autonomic nervous system dysfunction. Epigenetic dysregulation has been implicated in PTHS, prompting the investigation of a DNA methylation (DNAm) "episignature" specific to PTHS for diagnostic purposes and variant reclassification and functional insights into the molecular pathophysiology of this disorder. A cohort of 67 individuals with genetically confirmed PTHS and three individuals with intellectual disability and a variant of uncertain significance (VUS) in TCF4 were studied.

Analysis of Serum Free Thyroxine Concentrations in Healthy Term Neonates Underlines Need for Local and Laboratory-Specific Reference Interval: A Systematic Review and Meta-Analysis of Individual Participant Data.

Initial evaluation of the hypothalamus-pituitary-thyroid axis is done by measuring serum free thyroxine (fT4) and thyrotropin concentrations. For correct interpretation of these measurements, reliable age-specific reference intervals (RIs) are fundamental. Since neonatal fT4 RIs conforming to the Clinical and Laboratory Standards Institute guidelines are not available for all assays, we set out to create literature-based uniform age-specific neonatal fT4 RIs that may be used for every assay.

Aberrant PRDM2 methylation as an early event in serrated lesions destined to evolve into microsatellite-instable colorectal cancers.

Up to 30% of colorectal cancers (CRCs) develop from sessile serrated lesions (SSLs). Within the serrated neoplasia pathway, at least two principally distinct oncogenetic routes exist generating microsatellite-stable and microsatellite-instable CRCs, respectively. Aberrant DNA methylation (DNAm) is found early in the serrated pathway and might play a role in both oncogenetic routes.

Diagnostic utility and reporting recommendations for clinical DNA methylation episignature testing in genetically undiagnosed rare diseases.

Purpose: This study aims to assess the diagnostic utility and provide reporting recommendations for clinical DNA methylation episignature testing based on the cohort of patients tested through the EpiSign Clinical Testing Network.

Methods: The EpiSign assay utilized unsupervised clustering techniques and a support vector machine-based classification algorithm to compare each patient's genome-wide DNA methylation profile with the EpiSign Knowledge Database, yielding the result that was reported. An international working group, representing distinct EpiSign Clinical Testing Network health jurisdictions, collaborated to establish recommendations for interpretation and reporting of episignature testing.

DNA methylation episignature, extension of the clinical features, and comparative epigenomic profiling of Hao-Fountain syndrome caused by variants in USP7.

Purpose: Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder caused by pathogenic variants in USP7. HAFOUS is characterized by developmental delay, intellectual disability, speech delay, behavioral abnormalities, autism spectrum disorder, seizures, hypogonadism, and mild dysmorphic features. We investigated the phenotype of 18 participants with HAFOUS and performed DNA methylation (DNAm) analysis, aiming to generate a diagnostic biomarker.

Functional Insight into and Refinement of the Genomic Boundaries of the -Neurodevelopmental Disorder Episignature.

(Jumonji, AT-rich interactive domain 2) haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. It is characterized by intellectual disability, developmental delay, autistic features, behavior abnormalities, cognitive impairment, hypotonia, and dysmorphic features. acts as a transcriptional repressor protein that is involved in the regulation of histone methyltransferase complexes.

Peripheral Blood DNA Methylation Signatures and Response to Tofacitinib in Moderate-to-severe Ulcerative Colitis.

Introduction: Predictive biomarkers for treatment efficacy of ulcerative colitis [UC] treatments are lacking. Here, we performed a longitudinal study investigating the association and potential predictive power of genome-wide peripheral blood [PB] DNA methylation signatures and response to tofacitinib treatment in UC.

Methods: We recruited moderate-to-severe UC patients starting tofacitinib treatment, and measured PB DNA methylation profiles at baseline [T1], after 8 weeks [T2], and in a subset [n = 8] after a median of 20 weeks [T3] using the Illumina Infinium HumanMethylation EPIC BeadChip.

Faecal Microbiota transplantation affects liver DNA methylation in Non-alcoholic fatty liver disease: a multi-omics approach.

Individuals with nonalcoholic fatty liver disease (NAFLD) have an altered gut microbiota composition. Moreover, hepatic DNA methylation may be altered in the state of NAFLD. Using a fecal microbiota transplantation (FMT) intervention, we aimed to investigate whether a change in gut microbiota composition relates to altered liver DNA methylation in NAFLD.

DNA methylation episignature and comparative epigenomic profiling of HNRNPU-related neurodevelopmental disorder.

Purpose: HNRNPU haploinsufficiency is associated with developmental and epileptic encephalopathy 54. This neurodevelopmental disorder is characterized by developmental delay, intellectual disability, speech impairment, and early-onset epilepsy. We performed genome-wide DNA methylation (DNAm) analysis in a cohort of individuals to develop a diagnostic biomarker and gain functional insights into the molecular pathophysiology of HNRNPU-related disorder.

Expression Quantitative Trait Methylation Analysis Identifies Whole Blood Molecular Footprint in Fetal Alcohol Spectrum Disorder (FASD).

Fetal alcohol spectrum disorder (FASD) encompasses neurodevelopmental disabilities and physical birth defects associated with prenatal alcohol exposure. Previously, we attempted to identify epigenetic biomarkers for FASD by investigating the genome-wide DNA methylation (DNAm) profiles of individuals with FASD compared to healthy controls. In this study, we generated additional gene expression profiles in a subset of our previous FASD cohort, encompassing the most severely affected individuals, to examine the functional integrative effects of altered DNAm status on gene expression.

Epigenome-wide association study of plasma lipids in West Africans: the RODAM study.

Background: DNA-methylation has been associated with plasma lipid concentration in populations of diverse ethnic backgrounds, but epigenome-wide association studies (EWAS) in West-Africans are lacking. The aim of this study was to identify DNA-methylation loci associated with plasma lipids in Ghanaians.

Methods: We conducted an EWAS using Illumina 450k DNA-methylation array profiles of extracted DNA from 663 Ghanaian participants.

Long-term Temporal Stability of Peripheral Blood DNA Methylation Profiles in Patients With Inflammatory Bowel Disease.

Background & Aims: There is great current interest in the potential application of DNA methylation alterations in peripheral blood leukocytes (PBLs) as biomarkers of susceptibility, progression, and treatment response in inflammatory bowel disease (IBD). However, the intra-individual stability of PBL methylation in IBD has not been characterized. Here, we studied the long-term stability of all probes located on the Illumina HumanMethylation EPIC BeadChip array.

DNA methylation episignatures: insight into copy number variation.

In this review we discuss epigenetic disorders that result from aberrations in genes linked to epigenetic regulation. We describe current testing methods for the detection of copy number variants (CNVs) in Mendelian disorders, dosage sensitivity, reciprocal phenotypes and the challenges of test selection and overlapping clinical features in genetic diagnosis. We discuss aberrations of DNA methylation and propose a role for episignatures as a novel clinical testing method in CNV disorders.

Cohort profile: Research on Obesity and Diabetes among African Migrants in Europe and Africa Prospective (RODAM-Pros) cohort study.

Purpose: The Research on Obesity and Diabetes among African Migrants (RODAM) prospective (RODAM-Pros) cohort study was established to identify key changes in environmental exposures and epigenetic modifications driving the high burden of cardiovascular disease (CVD) risk among sub-Saharan African migrants.

Participants: All the participants in the RODAM cross-sectional study that completed the baseline assessment (n=5114) were eligible for the follow-up of which 2165 participants (n=638 from rural-Ghana, n=608 from urban-Ghana, and n=919 Ghanaian migrants in Amsterdam, the Netherlands) were included in the RODAM-Pros cohort study. Additionally, we included a subsample of European-Dutch (n=2098) to enable a comparison to be made between Ghanaian migrants living in the Netherlands and the European-Dutch host population.

An explorative epigenome-wide association study of plasma renin and aldosterone concentration in a Ghanaian population: the RODAM study.

Background: The epigenetic regulation of the renin-angiotensin-aldosterone system (RAAS) potentially plays a role in the pathophysiology underlying the high burden of hypertension in sub-Saharan Africans (SSA). Here we report the first epigenome-wide association study (EWAS) of plasma renin and aldosterone concentrations and the aldosterone-to-renin ratio (ARR).

Methods: Epigenome-wide DNA methylation was measured using the Illumina 450K array on whole blood samples of 68 Ghanaians.