DNA methylation biomarkers of intellectual/developmental disability across the lifespan

Journal of Neurodevelopmental Disorders, Journal Year: 2025, Volume and Issue: 17(1)

Published: Feb. 19, 2025

Abstract Epigenetic mechanisms, including DNA methylation, act at the interface of genes and environment by allowing a static genome to respond adapt dynamic during lifespan an individual. Genome-wide methylation analyses on wide range human biospecimens are beginning identify epigenetic biomarkers that can predict risk intellectual/developmental disabilities (IDD). methylation-based signatures becoming clinically useful in categorizing benign from pathogenic genetic variants following exome sequencing. While marks differ tissue source, recent studies have shown accessible perinatal tissues, such as placenta, cord blood, newborn blood spots, cell free may serve surrogate tissues for testing relevant understanding genetic, environmental, gene interactions developing brain. These also provide important information about biological pathways become dysregulated prior disease progression could be used develop early pharmacological interventions. Future applications involve preventative screenings using pregnancy or period IDDs other neurodevelopmental disorders. adolescence adulthood likely tracking aging co-occurring health conditions across lifespan. In conclusion, expected more common clinical diagnoses IDD, improve complex IDD etiologies, endpoints trials, monitor potential concerns individuals with they age.

Language: Английский

Sex-specific DNA methylation signatures of autism spectrum disorder from whole genome bisulfite sequencing of newborn blood

Biology of Sex Differences, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 30, 2025

Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions currently diagnosed through behavioral assessments in childhood, though neuropathological changes begin utero. ASD more commonly males, disparity attributed to both biological sex differences and diagnostic biases. Identifying molecular biomarkers, such as DNA methylation signatures, could provide objective screening for ASD-risk newborns, allowing early intervention. Epigenetic dysregulation has been reported multiple tissues from newborns who are later with ASD, but this the first study investigate sex-specific signatures newborn blood, an accessible widely banked tissue. We assayed blood typically developing (TD) individuals (discovery set n = 196, replication 90) using whole genome bisulfite sequencing (WGBS). Sex-stratified differentially methylated regions (DMRs) were assessed replication, comparisons by sex, overlaps DMRs other tissues, enrichment processes SFARI genes. found that sexes significantly replicated independent cohort enriched hypomethylation compared TD samples, well location promoters, CpG islands, island shores. By comparing female male we most sex-associated also individuals, alongside additional ASD-specific differences. Female-specific X chromosomal location. Across sexes, overlapped umbilical cord placenta not post-mortem cerebral cortex. all (females) known genes (both sexes). Overall, identified signature supported protective effect highlighted convergence epigenetic genetic newborns. Despite study's limitations, particularly sample sizes, our results demonstrate potential emphasize importance sex-stratification future studies.

Language: Английский

Hippocampal and peripheral blood DNA methylation signatures correlate at the gene and pathway level in a mouse model of autism

Human Molecular Genetics, Journal Year: 2023, Volume and Issue: 32(24), P. 3312 - 3322

Published: Aug. 31, 2023

Autism spectrum disorders (ASD) are polygenic multifactorial influenced by environmental factors. ASD-related differential DNA methylation has been found in human peripheral tissues, such as placenta, paternal sperm, buccal epithelium, and blood. However, these data lack direct comparison of levels with brain tissue from the same individual to determine extent that tissues surrogates for behavior-related disorders. Here, whole genome profiling at all possible sites throughout mouse (>25 million) both blood revealed novel insights into systemic contributions ASD. Sixty-six differentially methylated regions (DMRs) share genomic coordinates two many which linked risk genes neurodevelopmental intellectual disabilities (e.g. Prkch, Ptn, Hcfc1, Mid1, Nfia). Gene ontological pathways a significant number common terms between (N = 65 terms), nearly half (30/65) were associated brain/neuronal development. Furthermore, seven DMR-associated among contain methyl-sensitive transcription factor sequence motifs within DMRs tissues; four them (Cux2, Kcnip2, Fgf13, Mrtfa) binding (HES1/2/5, TBX2 TFAP2C), suggesting influences factors required gene expression. Together, findings suggest is good surrogate support contributes altered regulation pathogenesis

Language: Английский