DNA Methylation and Neurodevelopmental Outcomes of Preterm Born Children:
A Systematic Review
By: Meaghan Sowers
Senior Honors Thesis
School of Nursing
University of North Carolina at Chapel Hill
April 28, 2020
Table of Contents
Study Inclusion Criteria...3
Study Selection and Data Extraction...3
Neurodevelopmental outcomes and DNA methylation...6
Children born preterm < 30 weeks’ gestation...6
Children born extremely preterm at < 28 weeks’ gestation...8
Comparison between children born full-term vs preterm...9
Background: Preterm infants are at an increased risk of developing detrimental
neurodevelopmental outcomes. Although substantial research exists on DNA methylation related
to growth and development of newborns, there are currently no systematic reviews focusing on
how epigenetic dysregulation of DNA methylation is associated with neurodevelopmental
outcomes in preterm children.
Objectives: We sought to understand how DNA methylation and their associated genes play a role in the neurodevelopmental outcomes of preterm infants (<37 weeks gestational age).
Methods: We searched electronic databases PubMed, CINAHL, Embase, Scopus, and Web of Science in this systematic review. We identified 2,312 studies. Based on pre-determined criteria,
we reviewed full-text of 39 studies, and five were included in the final sample.
Results: Increased methylation of NR3C1, F10, PLA2G4E, TRIM9, GRIK3, ADCY7,CABLES,
GNAO1, PRKCZ, FDHI3, RHOF, SH3BP5, STX1A, HSP90AA1 and CRHBP and
hypomethylation of HSD11B2 are all associated with increased risk for cognitive impairment in preterm infants. Whereas, hypermethylation of FKBP5, CRHR2 and TH are associated with a decreased risk in cognitive impairment.
Conclusion: Future research should further examine these genes and their methylation patterns to be used as biomarkers for the early diagnosis of neurodevelopmental outcomes in children
Preterm birth (PTB), defined as delivery at < 37 weeks of gestation, is a pressing public
health concern and the leading cause of infant morbidity and mortality worldwide (Mathews and
Driscoll 2017; Harrison and Goldenberg 2016; Purisch and Gyamfi-Bannerman 2017; Behnia et
al., 2015). In the United States, PTB accounts for approximately 11% of infants born
prematurely, with an annual cost of $26 billion (Purisch and Gyamfi-Bannerman 2017;
Fitzgerald, Boardman and Drake et al., 2018; Behnia et al., 2015). Approximately 30-40% of
children born prematurely will experience some level of neurodevelopmental impairment such as
cerebral palsy, autism spectrum disorder (ASD), epilepsy, intellectual disability and many other
learning, visual or motor disorders (Luu et al. 2017; Hirschberger et al. 2018; Serenius et al.
2016; Synnes and Hicks 2018; Joseph et al. 2016). Along with the financial costs, these
outcomes and complications can put emotional stress on preterm children and their families.
While a diagnosis at birth would be beneficial to these families, it is not currently possible.
Identification of molecular signatures predictive of neurodevelopmental impairment
related to prematurity is urgently needed. Identifying and locating molecular mechanisms and
biomarkers is essential for propelling research further to create early screening techniques to
detect neurodevelopmental outcomes before they become apparent. The impact of early
screening for neurodevelopmental disorders can assist in preparing parents, guardians, or
caregivers for a potential diagnosis. Increasing evidence supports a genetic link to risk for
atypical development; however, no genomic risk profiles are currently used for infants without
apparent genetic disorders (Mitchell, 2015; Cardosa et al., 2019; Blair, Pickler and Anderson,
Tyrosine Kinase, Neuregulin 3, and Solute Carrier Family 6 Member 4) have associations with
neurodevelopmental outcomes in multiple, high-quality studies (Burdick, Debrosse, Kane,
Lencz, and Malhotra, 2010; Lin et al., 2012; Kao et al., 2010; Meier et al., 2013; Tost et al.,
2014; Beevers, Wells, Ellis, and McGreary, 2009; Brummelte, Galea, Devlin, and Oberlander,
2013; Kobiella et al., 2011). It is understood that stressors early in life, such as PTB, can interact
with the genome and result in alterations in gene function (Wu et al., 2019; Burris, Baccarelli, Wright and Wright, 2015). DNA methylation can result from the interaction with stressors and the environment and has been associated with neurodevelopmental outcomes in children born
preterm (Aprón et al., 2017; Everson et al., 2019; Meakin et al., 2018; Lester et al., 2015; Tilley
et al., 2018; Sparrow et al., 2016; Bromer et al., 2012; Lee and Sawa, 2014). DNA methylation,
an important epigenetic mechanism that can regulate gene expression without changing DNA
sequence, is essential for cell identification and differentiation (Nugent and Bale, 2015; Bromer
et al., 2012; Conradt et al., 2013; Marsit, Maccani, Padbury and Lester, 2012). Although DNA
methylation is a needed mechanism for regulation of the genome, it can also be associated with
unthwarted neurodevelopmental disorders.
Therefore, the purpose of this systematic review is to evaluate and understand how DNA
methylation, and associated genes, play a role in the neurodevelopmental outcome of preterm
infants (<37 weeks gestational age). In addition, this review will help identify consistent DNA
methylation markers across studies, inform next steps to guide identification of predictive
biomarkers of PTB-related neurodevelopmental outcomes and inform clinical practices in
genomics screening. This review will function to move research forward in identifying essential
This systematic review follows the standards recommended in the Preferred Reporting
Items for Systematic Reviews and Meta-Analysis guideline (Moher et al. 2015). We focused on
studies that investigated the relationship between epigenetics and neurodevelopment outcomes
in preterm children.
Study Inclusion Criteria
Studies needed to investigate the relationships between DNA methylation and
neurodevelopmental outcomes of children born preterm in order to be considered for inclusion.
We defined preterm birth occurring at a gestational age of 37 weeks or less. Neurodevelopmental
outcomes considered for inclusion were cognitive impairment, cerebral palsy, autism and
epilepsy (Hirschberger et al., 2018). Studies with animal subjects were excluded.
We identified studies through PubMed, CINAHL, Embase, Scopus, and Web of Science.
A comprehensive search string was applied to all five databases to collect studies: Premature
birth OR infant OR premature OR preterm OR prematurity AND epigenesis, genetic OR gene
expression OR DNA Methylation OR epigenetics OR epigenesis OR DNA methylation OR
DNA methylations OR gene expression OR gene expressions AND Neurodevelopmental
Disorders OR Cerebral Palsy OR Nervous System OR neurodevelopment OR
neurodevelopmental OR developmental disability OR developmental disabilities OR intellectual
disability OR intellectual disabilities OR cerebral palsy OR autism OR autistic OR nervous
Studies were selected using the four-phase process for systematic reviews recommended
by the PRISMA guidelines (Figure 1) (Moher et al., 2015). After identifying 5,398 studies and
removing duplicates, 2,312 titles and abstracts from identified studies were screened for
eligibility and 2,272 studies were excluded. The full text of the remaining 40 studies was
retrieved and screened for eligibility. Reasons for exclusion for the 35 non-eligible studies were
recorded. In the final phase, four studies from the database search and one study from the manual
search met all eligibility criteria and were selected for data extraction. Data from included
literature was extracted into a template that included first author, publication year, sample size,
sample characteristics, graphic location, neurodevelopmental outcomes, neurodevelopmental
measure, time of measure, biological sample, DNA methylation method, p-values, multiple
testing, cell heterogeneity, main results, limitations and implications. For thoroughness, a second
Figure 1. Study Flow Diagram
Full-text articles excluded, with reasons
(n = 35)
16 Wrong study design 6 Wrong intervention
5 Wrong indication 3 Wrong patient
population 2 Wrong outcomes
1 Duplicate 1 Wrong setting 1 Article no longer
available Studies included in
quantitative synthesis (meta-analysis)
(n = 5) Studies included in qualitative synthesis
(n = 5)
Full-text articles assessed for eligibility
(n = 40)
Records excluded (n = 2272) Records screened
(n = 2312)
Records after duplicates removed (n = 2312)
Additional records identified through other sources
(n = 1) Id en tifi ca tio
El i gi b ili t y
In cl ud ed Sc re en in g
Records identified through database searching
All five papers were published in the last five years. Gestational age of participants in the
studies ranged from 23-35 weeks. Two studies enrolled only extremely preterm infants (<28
weeks gestational age) (Meakin et al., 2018; Tilley et al., 2018). Cognitive function was the
primary neurodevelopmental outcome studied and was measured in all five studies. In two
studies, DNA methylation from a placental biopsy was used (Meakin et al., 2018; Tilley et al.,
2018). DNA methylation from buccal swabs was used in two studies (Everson et. al., 2019;
Lester et al., 2015), and the remaining study used blood (Aprón et al., 2017). Genome-wide
analysis were conducted for four studies and one conducted a study on candidate genes (Table
Neurodevelopmental outcomes and DNA methylation
These results are organized by year of publication and preterm birth gestational weeks,
respectively. Each one is focused on their purpose, neurodevelopmental and DNA methylation
outcome measures and a summary of key findings.
Children born preterm < 30 weeks’ gestation
Lester et al.’s (2015) goal was to determine if methylation of certain candidate genes are
associated with neurobehavioral profiles in preterm infants. This article studied how DNA
methylation of Hydroxysteroid 11-Beta Dehydrogenase 2 (HSD11B2) and Nuclear Receptor
using the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS). This scale can
profile preterm infants into a high-risk and low-risk category which predicts long-term
developmental outcomes. Based on the NNNS scores, 38 out of 67 infants were categorized into
a low-risk group and the remaining 29 infants were put into the high-risk group for problematic
neurobehavior. For NR3C1 at CpG 3, the high-risk group showed double the amount of
methylation compared to the low-risk group. In contrast, DNA methylation for HSD11B2 at the CpG 3 site was lower for high-risk infants compared to the low-risk group. The DNA
methylation patterns of these genes and how they are reflected in the NNNS profile is an
indication that these genes and the CpG sites can be used as a biomarker for diagnostic testing on
preterm infants to determine cognitive function outcomes.
Everson et al. (2019) conducted a genome-wide study on the epigenetic differences
of infant neurobehavior based on the relationship between DNA methylation in the placenta of
preterm newborns (<30 weeks’ gestation) and NNNS scores. Based on the NNNS scores,
subjects were separated into an optimal profile group and an atypical profile group. Areas of
higher methylation was found among CpG sites in the newborns with atypical profile. The F10
gene had the strongest association with the NNNS scores, along with other genes that are linked
to neurobehavioral disorders, such as, phospholipase A2 group IVE (PLA2G4E), tripartite motif containing 9 (TRIM9), and glutamate ionotropic receptor kainate type subunit 3 (GRIK3). The authors highlight how their study illustrates the important link between DNA methylation of
Children born extremely preterm at < 28 weeks’ gestation
Meakin et al. (2018) studied how placental CpG methylation could predict cognitive
outcomes at the age of 10 for children born before 28 weeks’ gestation. A total of 14 genes were
found to play a key role in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis.
These genes have many biological functions in the placenta that can influence fetal growth and
development as well as later-life cognition. In this study, the participants were from the
Extremely Low Gestational Age Newborn (ELGAN) study. They looked at cognitive
development at the age of 10 for children born prematurely. The School-Age Differential Ability
Scales-II (DAS-II) and NEPSY-II were used to assess for general cognitive ability. They
discovered CpG methylation 41 CpG probes within 10 HPA genes were associated with
moderate/severe cognitive impairment. Increased CpG methylation of the Nuclear Receptor
Subfamily Group 3C Member 1 (NR3C1), the Heat Shock Protein 90 Alpha Family Class A
Member 1 (HSP90AA1), and the Corticotropin Releasing Hormone Binding Protein (CRHBP)
were found to be associated with moderate/severe cognitive impairment. However, increased
CpG methylation of the FK506 Binding Protein 5 (FKBP5), the 3’ UTR region of Corticotropin
Releasing Hormone (CRH), the Corticotropin Releasing Hormone Receptor 2 (CRHR2), and
Tyrosine Hydroxylase (TH) showed a decreased risk of cognitive impairment. Overall, the authors were able to reveal that increases in placental CpG methylation of HPA-axis related
genes were associated with both a higher and lower risk of cognitive impairment at the age of
hypermethylation of CpG sites in the placenta predicts cognitive impairment at ten years of age
for children born before 28 weeks’ gestation. Out of 84 subjects, 18 had intellectual deficits, 18
had autism spectrum disorder without intellectual deficits and 48 had neither autism spectrum
disorder nor intellectual deficits. Cognitive assessment was assessed using School-Age
Differential Ability Scales-II (DAS-II) and NEPSY-II. Normal cognitive function was identified
in 34% of the ELGAN cohort, 41% had low to normal cognition, 17% were moderately impaired
and 8% had severe cognitive impairment. Placental DNA methylation of 250 CpG sites of 217
unique genes were compared between two groups: spontaneous extremely preterm birth (EPTBs)
and indicated EPTBs. Seventeen of the 250 differentially methylated CpGs predicted moderate
to severe cognitive impairment at age ten for spontaneous EPTB. Higher amounts of methylation
were positively proportional to increased cognitive impairment. The genes that showed the most
significance in this study were Adenylate cyclase 7 (ADCY7), Cdk5 and Abl enzyme substrate 1 (CABLES1), G protein subunit alpha o1 (GNAO1), protein kinase C zeta (PRKCZ), retional
dehydrogenase 13 (RDH13), ras homolog family member F, filopodia associated (RHOF), SH3
domain binding protein 5 (SH3BP5), and syntaxin 1A (STX1A). Each of these genes predicted that a 1% increase in methylation at their probe sites increased the odds of developing moderate
or severe cognitive impairment at age ten by 4-7%. The 17 CpGs studied between spontaneous
and indicated EPTB could be used as clinical epigenomic biomarkers that can perinatally predict
late-life cognitive impairments.
Aprón et al., (2017) conducted a genome-wide study that compares methylation patterns
of full-term newborns (> 37 weeks’ gestation) versus preterm newborns (< 34 weeks’ gestation).
The authors identified CpG methylation patterns of 317 CpGs (corresponding to 232 genes) to be
associated with PTB. Out of all the CpG sites, the one found to be most significant and showed
the largest methylation difference between the preterm and full-term newborns was located in the
5’ UTR of the corresponding gene Solute Carrier Family 6 Member 3 (SLC6A3). Developmental
outcomes were assessed at 24 and 36 months of age using the Bayley Scale of Infant
Development (BSID) version II and III. This assessment tool is used to predict
neurodevelopmental outcomes in children. Overall, for each subset of the BSID, preterm infants
scored significantly lower compared to the full-term infants. The results of this study also found
that in preterm infants there is a relationship between increased SLC6A3 methylation and lower BSID scores which can predict later-life neurodevelopmental impairments, suggesting that this
gene has a potential epigenetic biomarker that could play a key role in the early diagnosis of
We set out to conduct a systematic review of the literature on how neurodevelopmental
outcomes of preterm infants are attributed to DNA methylation. DNA methylation is a biological
process by which methyl groups are added to the DNA molecule. Dysregulation of this process is
believed to be associated with detrimental health outcomes, such as neurodevelopmental
impairments. We found an array of protein coding genes that, when hypermethylated or
hypomethylated, cause an increased risk of cognitive impairment.
Lester et al. 2015 and Everson et al. 2019 both studied neurobehavioral profiles of
preterm infants using the NNNS scale to compare the DNA methylation patterns of genes and
their CpG sites. The hypermethylation of genes NR3C1, F10, PLA2G4E, TRIM9, GRIK3 were found to be most significantly correlated with infants at high-risk of developing a
neurobehavioral disorder based on NNNS scores (Lester et al., 2015; Everson et al., 2019). On
the other hand, the CpG site on the HSD11B2 gene was found to be hypomethylated in the high-risk group (Lester et al., 2015). Tilley et al. 2018 and Meakin et al. 2018 both studied placental
DNA methylation patterns in the ELGAN study group. The DAS-II and NEPSY-II scales were
used to assess cognitive function of their participants at age 10. In their studies, the
hypermethylated genes shown to have the most significant correlation to moderate/severe
cognitive impairment was ADCY7, CABLES1, GNAO1, PRKCZ, RDHI3, RHOF, SH3BP5,
NR3C1, HSP90AA1, and CRHBP (Tilley et al., 2018; Meakin et al., 2018).
Interestingly, Lester et al. 2015 and Meakin et al. 2018 both found the hypermethylation
Conradt et al. 2013 conducted a study on DNA methylation and neurodevelopmental outcomes
on children born full-term. One of their findings identified an increase in methylation of the
NR3C1 gene in mothers who were experiencing depression during pregnancy. The increase in the methylation of NR3C1 was affiliated with a lower NNNS score which indicates an increased risk in developing cognitive impairment. However, an increase in the methylation of genes does
not always correlate to an increased risk of cognitive impairment. On the contrary, Meakin et al.
(2018) discovered that hypermethylation of FKBP5, CRHR2, and TH CpG sites lead to a decreased risk in cognitive impairment at age 10.
Aprón et al. 2017 was the only study that used blood samples to study DNA methylation
patterns and the BSID II and III scales to assess for neurodevelopmental outcomes. In their
genome-wide study, they discovered that hypermethylation of SLC6A3 was more prevalent in preterm infants compared to full term infants and related to lower BSID scores. DNA
methylation are important regulators of tissue differentiation, contributing to processes of both
development and detrimental health outcomes. Considering the differences in tissues use by the
studies evaluated in this review (2 used placenta tissue, 2 used buccal swabs, 1 used blood
samples), we need to be cautious on comparing the results between studies derived from
different tissues. One cannot fully discard that similarities and/or differences observed in DNA
methylation patterns are not just due to differences in tissue/cell composition. Further studies
need to be conducted to explore how to interpret and compare findings from different tissues.
used as biomarkers in identifying and diagnosing various neurodevelopmental outcomes. Our
current clinical approaches used to diagnose neurodevelopmental disorders are based on clinical
presentation rather than diagnosing from biological processes and are often limited and lack
precision (Mullin et al., 2013), because not only do symptoms for different types of
neurodevelopmental disorders overlap, but a diagnosis is often not made until middle or late
childhood (Reiss, 2009). Therefore, it is imperative that research steps forward into the
innovation of identifying these epigenetic processes as a diagnostic tool for neurodevelopmental
We had a limited number of studies to include in our systematic review due to the scarce amount
of research on this topic. There was also not a wide variety of biological samples included in this
study, such as, cord blood or maternal tissue. Neurodevelopmental outcomes such as Autism,
Cerebral Palsy and Epilepsy were not studied due to the limited amount of research on the
methylation of their associated genes. There are many other genes that were not covered in this
study that are likely involved in the process of neurodevelopmental outcomes. The children’s
ages in these studies were limited to early infancy, from birth to 36 months old, and 10 years of
age. Due to the studies involving a highly specific population, some studies had a low or
This is the first systematic review to examine how DNA methylation correlates to
neurodevelopmental outcomes of preterm infants. There are several CpG sites on essential genes
found to be associated with later-life cognitive impairment. Both hypermethylated and some
hypomethylated CpG sites that were present in children born preterm were associated with
cognitive impairment outcomes. Overall, these epigenetic mechanisms have the potential to
recognize these genes as biomarkers in the early identification and diagnosis of possible
Study (DOI) Sample size (n) Sample
Characteristics GeographicLocation NeurodevelopmentalOutcome(s) Neurodevelopmental Assess measureTime of
Aprón et al., 2017 n = 46 (24 PT & 22 FT) PT Gestational age <34
FT Gestational age >37 weeks.
PT Birthweight <1500g
Madrid, Spain La Paz University Hospital
behavioral & learning disorders: ADHD, Cerebral palsy
Bayley scale of Infant Development version II and BSID III motor & mental
24 & 36 months
Everson et al., 2019 n = 709 infants (enrolled)
n = 679 (neurobehavioral assessment)
n = 624 (epigenomic screening)
Gestational age <30 weeks
9 university-affiliated NICUs: Providence, RI Grand Rapids, MI Kansas City, MO Honolulu, HI Winston-Salem, NC Torrance and Long Beach, CA
Neonatal neurobehavior Neonatal Intensive Care
Unit Network Neurobehavioral Scale (NNNS)
near term-equivalent age
Tilley et al., 2018 n=84 (59 spontaneous
EPTB & 25 indicated EPTB)
Gestational age 23-28 weeks
USA (multi-site) Cognitive function School-Age Differential Ability
Scales II (DAS-II) scales; NEPSY-II
10 years of age
Lester et al., 2015 n = 67 Gestational age 23-35
Birthweight, 480-1495 g.
NICU at Women & Infants Hospital of Rhode Island
Cerebral Palsy, Cognitive and Motor impairment
Neonatal Intensive Care
Unit Network Neurobehavioral Scale (NNNS)
3-4 days before discharge
Meakin et al., 2018 n = 228 Gestational age <28
weeks (average =25.7 weeks).
60.2% males, 39.8% females. 69.3% normal or low normal cognitive function. 30.7% moderate/severe cognitive impairment. 42% multigestation. 16% assisted reproductive technology (ART)
USA (multi-site) Cognitive function School-Age Differential Ability
Scales II (DAS-II) scales; NEPSY-II
Study (DOI) Biological Sample
DNA methylation measurement
DNAm scale Gene(s)
Aprón et al., 2017 Blood (12
months of age)
Bisulfite-treated genomic DNA was amplified and hybridized using the Infinium HumanMethylation450 BeadChip
Genome wide 317 CpGs were
identified. SLC6A3 was the main CpG
Yes Yes Yes
Everson et al., 2019 Buccal Swabs DNA was quantified using the Quibit
Fluorometer and aliquoted into a standardized concentration for subsequent analyses. DNA samples were plated randomly across 96-well plates and provided to the Emory University Integrated Genomics Core for bisulfite modification using the EZ DNA Methylation Kit subsequent assessment of genome-wide DNAm using the Illumina MethylationEPIC Beadarray
Genome wide F10, PLA2G4E,
TRIM9 & GRIK3
Yes Yes Yes
Tilley et al., 2018
Isolated DNA was first bisulfite-converted using the EZ DNA methylation kit. Converted DNA was then hybridized onto the Illumina HumanMethylation450 BeadChip
Genome wide ADCY7,
CABLES1, GNAO1, PRKCZ, RDHI3, RHOF, SH3BP5, STX1A
Yes Yes Yes
Lester et al., 2015 Buccal Swabs Genomic DNA was extracted from oral
swab samples of each infant collected using Oragene Discover for assisted collection using the prepIT kit and subjected to bisulfite modification using the EZ DNA methylation
Candidate gene HSD11B2 &
Yes Yes N/A
Meakin et al., 2018 Placenta Isolated DNA was first
bisulfite-converted using the EZ DNA methylation kit. Converted DNA was then hybridized onto the Illumina HumanMethylation450 BeadChip
Genome wide CRHBP, NR3C1,
HSP90AA1, FKBP5, CRH, CRHR2, & TH
Yes Yes Yes
identify susceptible individuals and develop preventive and therapeutic measures. Further studies are necessary to confirm the interaction between gestational age as a cause of the changes or a causal role for SLC6A3 and genes related with this pathologic pathway.
BSID-II mental and motor scores showed that methylation and gestational age were significantly associated with this score in simple linear regressions
Peripheral white blood cells were used, which are not part of a tissue related to
Everson et al.,
2019 Differentially methylated CpGs at multiple genes linked to neural structure, function, or different neurobehavioral or
neurodegenerative conditions were found in infants with poorly regulated neurobehavioral profiles
A 10% false discovery rate was used to identify significantly differentially methylated CpG sites. Only one of the models yielded an FDR < 5%.
It is probable that some of identified epigenetic loci are false-positives.
Neonatal epigenetic variation may be informative for predicting infant neurobehavior and neurodevelopmental outcomes in order to maximize the potential benefits of interventions aimed at ameliorating long term deficits.
Methylation of F10, PLA2G4E, TRIM9, and GRIK3 are associated with NNNS scores that put infants at high risk for neurobehavioral disorders.
The combination of epigenomics and neurobehavior has potential for a personalized medicine approach for early detection of poor developmental outcomes.
Tilley et al., 2018
Methylation of genes in placental tissue predicts children's cognitive function at ten years of age
This study is focused on CpG methylation in the placenta only and would not have similar results to a study that focuses on CpG methylation in the fetal brain due to the fact that CpG methylation is tissue-specific.
CpG hypermethylation in placental tissue from spontaneous EPTB could mediate the relationship seen between PTB and adverse neurodevelopmental outcomes Hypermethylation in genes is associated with neuronal development
Hypermethylation of DMPs predicts cognitive function at ten years
of age. 5 of the 17 sites failed to reach significance in the sensitivity analysis due to the lowered
power of the analysis caused by the restricted sample size
DMPs identified between spontaneous and indicated EPTB can be further investigated and used as perinatal clinical
epigenomic biomarkers of later-life neurodevelopmental outcomes.
For each of these genes, a one percent increase in methylation at their respective probe sites predicted a 4-7% increase in the odds of moderate or severe cognitive impairment at age 10
Current standard practice relies on childhood cognitive tests to identify cognitive impairment. But, identification of neonates at highest risk for adverse neurodevelopmental outcomes could present opportunities for earlier interventions which can improve the outcomes of these children
Lester et al., 2015
Preterm infants are more prone to have increased cortisol levels and are at higher risk for more DNA methylation at CpG3 for NR3C1 and less methylation of CpG3 for HSD11B2--which can later lead to adverse neurodevelopmental outcomes.
Causal relations cannot be established because it is an associational study. This study does not indicate epigenetic mechanisms in the brain. Only 2 genes were studied, but more genes are likely involved in these processes.
A genome-wide study of DNA methylation would competent this study of candidate genes and further our understanding o neurobehavioral development.
Meakin et al., 2018
Of the 237 tested probes, 41 probes representing 10 HPA genes were identified to have CpG methylation that was significantly associated with moderate/severe cognitive impairment.
Study focused on CpG methylation of placenta only and not brain tissue. Environmental exposure data was not available for this study.
Future studies should integrate mRNA and protein expression with CpG methylation and environmental exposure data as it relates to epigenetic modification to provide more information on biomarkers for exposure and later-life cognitive
impairments. Increased CpG methylation of NR3C1, HSP90AA1 & CRHBP
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