DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome
Abstract
:1. Introduction
2. Results
2.1. Sensitivity and Specificity of FREE2m Analysis of NBS (Time-Point 1: Birth)
2.2. Epigenotype-Phenotype Correlations using NBS FREE2m (Time-Point 1: Birth)
2.3. Epigenotype-Phenotype Correlations using DBS FREE2m (Time-Point 2: Childhood)
2.4. Correlation between FMR1 mRNA and FREE2m Using NBS (at Birth) and DBS (during Childhood)
2.5. Longitudinal Changes in FREE2m from Birth to Childhood
3. Discussion
3.1. Epigenotype-Phenotype Associations
3.2. Screening and Diagnostic Potential
3.3. Sex Specific Differences in DNAm Longitudinal Trajectories in Blood
3.4. Limitations
4. Materials and Methods
4.1. Participants
4.2. Molecular Testing
4.3. Neuropsychological Testing
4.4. Statistical Analyses
5. Conclusions
6. Patents
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ADOS-2 | Autism Diagnostic Observation Schedule-Second Edition |
ASD | Autism Spectrum Disorder |
AUC | Area under the curve |
cFSIQ | Corrected Full Scale IQ |
CGG | Cytosine-Guanine-Guanine |
cVIQ | Corrected Verbal IQ |
CSS | Calibrated Severity Score |
cPIQ | Corrected Performance IQ |
DBS | Dried blood spots |
DNAm | DNA methylation |
FDR | False Discovery Rate |
FM | Full mutation |
FMRP | Fragile X Mental Retardation Protein |
FREE2 | Fragile X Related Epigenetic Element 2 |
FREE2m | Fragile X Related Epigenetic Element 2 methylation |
FXS | Fragile X syndrome |
ID | Intellectual Disability |
IQ | Intelligence Quotient |
MS-QMA | Methylation Specific-Quantitative Melt Analysis |
NBS | Newborn blood spots |
NS | Normal size |
PBMC | Peripheral Blood Mononuclear Cells |
PCR | Polyamerase Chain Reaction |
PM | Premutation |
PM/FM | Premutation/Full mutation |
ROC | Receiver operating characteristic curve |
RRB | Repetitive and Restricted Behaviours |
SA | Social Affect |
VCGS | Victorian Clinical Genetic Services |
WPPSI-III | Wechsler Preschool and Primary Scale of Intelligence—Third edition |
WISC-IV | Wechsler Intelligence Scale for Children—Fourth edition |
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FXS (FM + PM/FM) | FM only | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Male (n = 42) | Female (n = 23) | Male (n = 31) | Female (n = 21) | |||||||
N | Mean ± SD | N | Mean ± SD | p | N | Mean ± SD | N | Mean ± SD | p | |
Age at assessment a | 42 | 5.09 ± 4.60 | 23 | 5.02 ± 3.63 | 0.8103 | 31 | 5.17 ± 4.80 | 21 | 5.20 ± 4.12 | 0.8447 |
cFSIQ | 33 | 41.1 ± 18.4 | 18 | 61.3 ± 17.2 | 0.0004+ | 23 | 38.2 ± 19.3 | 16 | 58.6 ± 15.8 | 0.0013+ |
cPIQ | 33 | 47.3 ± 16.0 | 18 | 61.9 ± 16.0 | 0.0031+ | 23 | 45.6 ± 17.2 | 16 | 60.3 ± 15.9 | 0.0102+ |
cVIQ | 33 | 51.5 ± 14.8 | 18 | 68.3 ± 16.2 | 0.0005+ | 23 | 49.9 ± 15.4 | 16 | 65.8 ± 15.0 | 0.0028+ |
ADOS-2 CSS a | 42 | 6.00 ± 1.00 | 22 | 4.00 ± 3.00 | 0.0002+ | 31 | 6.00 ± 1.00 | 20 | 4.00 ± 2.75 | 0.0012+ |
SA CSS a | 42 | 6.00 ± 3.00 | 22 | 4.00 ± 3.00 | 0.0094+ | 31 | 6.00 ± 3.00 | 20 | 4.00 ± 2.75 | 0.0226+ |
RRB CSS a | 42 | 8.00 ± 3.00 | 22 | 7.00 ± 2.25 | 0.0012+ | 31 | 8.00 ± 3.00 | 20 | 7.00 ± 2.00 | 0.0207+ |
Gestational age a | 41 | 39.0 ± 3.00 | 23 | 39.0 ± 2.00 | 0.5256 | 30 | 38.0 ± 3.00 | 21 | 39.0± 2.00 | 0.2914 |
Medication use b | 42 | 38.1% | 23 | 26.1% | 0.4157 | 31 | 35.5% | 21 | 28.6% | 0.7650 |
Ethnicity b | 42 | 23 | 0.8537 | 31 | 21 | 0.8305 | ||||
White | 32 | 76.2% | 18 | 78.3% | 22 | 71.0% | 16 | 76.2% | ||
Other | 9 | 21.4% | 4 | 17.4% | 8 | 25.8% | 4 | 19.0% | ||
Not disclosed | 1 | 2.4% | 1 | 4.3% | 1 | 3.2% | 1 | 4.8% |
Male | Female | |||||||
---|---|---|---|---|---|---|---|---|
N | Mean | SD | p | N | Mean | SD | p | |
MS-QMA * | 20 | 0.56 a | 2.43 | 0.067 | 15 | –0.50 | 1.99 | 0.351 |
EpiTYPER # | 18 | –0.30 a | 1.22 | 0.286 | 15 | –0.76 a | 1.58 | 0.008 |
CpG 1 | 18 | –0.72 | 3.02 | 0.328 | 15 | –0.38 | 2.67 | 0.585 |
CpG 2 | 16 | –0.45 a | 2.01 | 0.326 | 13 | –1.06 | 1.13 | 0.006+ |
CpG 6/7 | 17 | –0.40 a | 1.79 | 0.332 | 12 | –1.06 | 1.64 | 0.047 |
CpG 8/9 | 17 | –0.12 | 3.91 | 0.897 | 14 | –1.56 | 2.11 | 0.016+ |
CpG 10-12 | 18 | –0.50 | 1.89 | 0.282 | 14 | –1.13 a | 1.73 | 0.001+ |
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Kraan, C.M.; Baker, E.K.; Arpone, M.; Bui, M.; Ling, L.; Gamage, D.; Bretherton, L.; Rogers, C.; Field, M.J.; Wotton, T.L.; et al. DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome. Int. J. Mol. Sci. 2020, 21, 7735. https://doi.org/10.3390/ijms21207735
Kraan CM, Baker EK, Arpone M, Bui M, Ling L, Gamage D, Bretherton L, Rogers C, Field MJ, Wotton TL, et al. DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome. International Journal of Molecular Sciences. 2020; 21(20):7735. https://doi.org/10.3390/ijms21207735
Chicago/Turabian StyleKraan, Claudine M, Emma K Baker, Marta Arpone, Minh Bui, Ling Ling, Dinusha Gamage, Lesley Bretherton, Carolyn Rogers, Michael J Field, Tiffany L Wotton, and et al. 2020. "DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome" International Journal of Molecular Sciences 21, no. 20: 7735. https://doi.org/10.3390/ijms21207735