A new study led by researchers at the UC Davis MIND Institute found a distinctive signature of DNA methylation in the umbilical cord blood of newborns who were eventually diagnosed with autism spectrum disorder (ASD). This signature mark covers regions of DNA and genes linked to early fetal neurodevelopment. The results may contain clues for early diagnosis and intervention.
We found evidence that an ASD DNA methylation signature exists in cord blood with specific regions consistently differentially methylated.
Janine LaSalle, lead author of the study and professor of microbiology and immunology at UC Davis
The study was published on October 14 in Genomic Medicine it also identified sex-specific epigenomic signatures that support TEA’s development and sex-biased roots.
The US Centers for Disease Control and Prevention (CDC) estimates that one in 54 children are diagnosed with ASD, a complex neurological condition linked to genetic and environmental factors. It is much more prevalent in men than women.
The role of the epigenome in the functioning of DNA
The epigenome is a collection of chemical compounds and proteins that tell DNA what to do. These compounds bind to DNA and modify its function. One of these compounds is CH3 (known as methyl group) that can lead to DNA methylation. DNA methylation can alter the activity of a DNA segment without changing its sequence. Differentially methylated regions (DMRs) are areas of DNA that have significantly different methylation status.
The epigenome compounds do not alter the DNA sequence, but they do affect the way cells use DNA instructions. These attachments are sometimes passed from cell to cell as the cells divide. They can also be passed on from one generation to the next. The neonatal epigenome has the potential to reflect previous interactions between genetic and environmental factors during early development. They can also influence future health outcomes.
Find factors in fetal cord blood that can predict autism
The researchers studied the development of 152 children born to mothers enrolled in the MARBLES and EARLI studies. These mothers had at least one older child with autism and were considered to be at high risk of having another child with ASD. When these children were born, the mothers’ umbilical cord blood samples were preserved for analysis. At 36 months, these children had diagnostic and developmental assessments. Based on this, the researchers grouped children into “typical development” (TD) or “with ASD”.
The researchers also analyzed the umbilical cord blood samples taken at birth. They performed the entire genome sequencing of these blood samples to identify an epigenomic signature or ASD mark at birth. They were looking for any DNA-epigenome binding patterns that could predict future diagnosis of ASD.
They divided the samples into discovery and replication sets and stratified them by sex. The discovery set included samples from 74 men (39 TD, 35 ASD) and 32 women (17 TD, 15 ASD). The replication set was obtained from 38 males (17 TD, 21 ASD) and eight females (3TD, 5 ASD).
Using the samples from the discovery set, the researchers sought to identify specific regions in the genomes linked to the diagnosis of ASD. They tested DNA methylation profiles for DMRs between ASD and TD cord blood samples. They mapped DMRs into genes and evaluated them for gene function, tissue expression, chromosome location and overlap with previous ASD studies. Subsequently, they compared the results between discovery and replication sets and between males and females.
Umbilical cord blood to reveal insights into ASD-related genes
The researchers identified sex-stratified DMRs that discriminated against ASD from TD cord blood samples in discovery and replication sets. They found that seven regions in men and 31 in women replicated, and 537 DMR genes in men and 1,762 DMR genes in women replicated by gene association. These DMRs identified in cord blood overlap with binding sites relevant to the development of the fetus’ brain. They showed cerebral and embryonic expression and location on the X chromosome and combined with previous epigenetic studies of ASD.
“The results of our study provide essential information for early diagnosis and intervention,” said LaSalle. “We were impressed with the ability of cord blood to reveal information about genes and pathways relevant to the fetal brain.”
The researchers pointed out that these results will require additional replication before being used for diagnosis. Their study serves as an important proof of principle that umbilical cord methyloma is informative about the future risk of ASD.
Mordaunt, C.E., et al. (2020) Umbilical cord DNA methyloma in newborns subsequently diagnosed with autism spectrum disorder reflects the early deregulation of neurodevelopment and X-linked genes, Genomic Medicine. doi.org/10.1186/s13073-020-00785-8.