DNA Methylation biomarkers of Intellectual/developmental Disability Across the Lifespan

Overview

Journal J Neurodev Disord

Publisher Biomed Central

Specialties Neurology
Psychiatry

Date 2025 Feb 19

PMID 39972408

Authors

Janine M LaSalle

Affiliations

Soon will be listed here.

Abstract

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

References

LaSalle J, Reiter L, Chamberlain S . Epigenetic regulation of UBE3A and roles in human neurodevelopmental disorders. Epigenomics. 2015; 7(7):1213-28. PMC: 4709177. DOI: 10.2217/epi.15.70. View

Loi M, Del Savio L, Stupka E . Social Epigenetics and Equality of Opportunity. Public Health Ethics. 2013; 6(2):142-153. PMC: 3712403. DOI: 10.1093/phe/pht019. View

Anderson R, Rothwell E, Botkin J . Newborn screening: ethical, legal, and social implications. Annu Rev Nurs Res. 2012; 29:113-32. PMC: 7768912. DOI: 10.1891/0739-6686.29.113. View

Ranta S, Zhang Y, Ross B, Takkunen E, Hirvasniemi A, de la Chapelle A . Positional cloning and characterisation of the human DLGAP2 gene and its exclusion in progressive epilepsy with mental retardation. Eur J Hum Genet. 2000; 8(5):381-4. DOI: 10.1038/sj.ejhg.5200440. View

Ladd-Acosta C, Daniele Fallin M . The role of epigenetics in genetic and environmental epidemiology. Epigenomics. 2015; 8(2):271-83. DOI: 10.2217/epi.15.102. View

Sharifi O, Haghani V, Neier K, Fraga K, Korf I, Hakam S . Sex-specific single cell-level transcriptomic signatures of Rett syndrome disease progression. Commun Biol. 2024; 7(1):1292. PMC: 11464704. DOI: 10.1038/s42003-024-06990-0. View

LaSalle J . X Chromosome Inactivation Timing is Not e: Implications for Autism Spectrum Disorders. Front Genet. 2022; 13:864848. PMC: 8959653. DOI: 10.3389/fgene.2022.864848. View

Letourneau A, Santoni F, Bonilla X, Sailani M, Gonzalez D, Kind J . Domains of genome-wide gene expression dysregulation in Down's syndrome. Nature. 2014; 508(7496):345-50. DOI: 10.1038/nature13200. View

Stefansson O, Sigurpalsdottir B, Rognvaldsson S, Halldorsson G, Juliusson K, Sveinbjornsson G . The correlation between CpG methylation and gene expression is driven by sequence variants. Nat Genet. 2024; 56(8):1624-1631. PMC: 11319203. DOI: 10.1038/s41588-024-01851-2. View

10.

Chiurazzi P, Pirozzi F . Advances in understanding - genetic basis of intellectual disability. F1000Res. 2016; 5. PMC: 4830215. DOI: 10.12688/f1000research.7134.1. View

11.

Olivier M, Asmis R, Hawkins G, Howard T, Cox L . The Need for Multi-Omics Biomarker Signatures in Precision Medicine. Int J Mol Sci. 2019; 20(19). PMC: 6801754. DOI: 10.3390/ijms20194781. View

12.

Mao R, Zielke C, Zielke H, Pevsner J . Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain. Genomics. 2003; 81(5):457-67. DOI: 10.1016/s0888-7543(03)00035-1. View

13.

Lo Y, Zhang J, Leung T, Lau T, Chang A, Hjelm N . Rapid clearance of fetal DNA from maternal plasma. Am J Hum Genet. 1999; 64(1):218-24. PMC: 1377720. DOI: 10.1086/302205. View

14.

Werren E, Peirent E, Jantti H, Guxholli A, Srivastava K, Orenstein N . Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations. Cell Death Dis. 2024; 15(5):379. PMC: 11140003. DOI: 10.1038/s41419-024-06768-6. View

15.

Ferilli M, Ciolfi A, Pedace L, Niceta M, Radio F, Pizzi S . Genome-Wide DNA Methylation Profiling Solves Uncertainty in Classifying Variants. Genes (Basel). 2022; 13(11). PMC: 9690023. DOI: 10.3390/genes13112163. View

16.

Aref-Eshghi E, Rodenhiser D, Schenkel L, Lin H, Skinner C, Ainsworth P . Genomic DNA Methylation Signatures Enable Concurrent Diagnosis and Clinical Genetic Variant Classification in Neurodevelopmental Syndromes. Am J Hum Genet. 2018; 102(1):156-174. PMC: 5777983. DOI: 10.1016/j.ajhg.2017.12.008. View

17.

LaSalle J . Epigenomic signatures reveal mechanistic clues and predictive markers for autism spectrum disorder. Mol Psychiatry. 2023; 28(5):1890-1901. PMC: 10560404. DOI: 10.1038/s41380-022-01917-9. View

18.

Husson T, Lecoquierre F, Nicolas G, Richard A, Afenjar A, Audebert-Bellanger S . Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders. Eur J Hum Genet. 2023; 32(2):190-199. PMC: 10853222. DOI: 10.1038/s41431-023-01474-x. View

19.

Salehi A, Ashford J, Mufson E . The Link between Alzheimer's Disease and Down Syndrome. A Historical Perspective. Curr Alzheimer Res. 2015; 13(1):2-6. PMC: 6368451. DOI: 10.2174/1567205012999151021102914. View

20.

Jones M, Farre P, McEwen L, MacIsaac J, Watt K, Neumann S . Distinct DNA methylation patterns of cognitive impairment and trisomy 21 in Down syndrome. BMC Med Genomics. 2013; 6:58. PMC: 3879645. DOI: 10.1186/1755-8794-6-58. View