Samantha Fine

 Introduction: The gene Succinate Dehydrogenase Flavoprotein Subunit A (SDHAP3) has epigenetic alterations in fetuses exposed to maternal smoking and other neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia, and down syndrome (DS)^1-4. Although maternal smoking during pregnancy and the above mentioned neurodevelopmental disorders have vastly different symptoms and underlying causes, all of these disorders affect brain development and more specifically, contain epigenetic alterations of the SDAHP3 gene. These neurodevelopmental disorders also have been implicated in mitochondrial dysfunction^5-7. The SDHAP3 gene, although precise function is unknown, is currently thought to be related to mitochondrial function⁵. Epigenetic research has grown significantly over the past decade and now, epigenetic biomarkers are being used for diagnostics and disease treatment⁸. There is no literature that relates epigenetic alterations of SDHAP3 to all of its neurodevelopmental disorders. By better understanding SDHAP3 and its epigenetic role in neurodevelopmental disorders and fetal exposure to maternal smoking, perhaps the pathophysiology and treatment of these disorders can be better understood. Methods: Brain tissue from second-trimester human fetuses exposed and unexposed to maternal smoking were analyzed with the Illumina Infinium Human Methylation 450BeadChip microarrays to locate genes with altered DNA methylation sites¹. Similarly, post-mortem brain tissue samples of individuals with and without ASD were analyzed with the same DNA methylation kit². Post-mortem brain tissue samples from individuals with and without DS were also analyzed with the same DNA methylation kit³. Post-mortem brain tissue samples from individuals with and without schizophrenia were also analyzed with the same DNA methylation kit⁴. Results: SDHAP3 was found to be hypomethylated in fetuses exposed to smoking in comparison to fetuses unexposed to smoking¹. SDHAP3 was hypermethylated in individuals with ASD in comparison to those without ASD². SDHAP3 was hypermethylated in individuals with DS in comparison to those without DS and similarly, SDHAP3 was hypermethylated in individuals with schizophrenia in comparison to those without schizophrenia^3,4. Conclusion: SDHAP3 gene is epigenetically altered in patients with schizophrenia, ASD, and DS, as well as fetuses exposed to maternal smoking. For any child with a neurodevelopmental disorder, early diagnosis and early intervention are key to improved outcomes⁹.  Because SDHAP3 was found to be a key gene to be epigenetically altered, this could be a potential biomarker or target for neurodevelopmental disorder therapy. Further investigation of SDHAP3 is needed, as it could clarify how epigenetic alterations of SDHAP3 contribute to the pathophysiology of schizophrenia, ASD, DS, and fetal exposure to smoking.

1. Chatterton Z, Hartley BJ, Seok MH, Mendelev N, Chen S, Milekic M, Rosoklija G, Stankov A, Trencevsja-Ivanovska I, Brennand K, Ge Y, Dwork AJ, Haghighi F. In utero exposure to maternal smoking is associated with DNA methylation alterations and reduced neuronal content in the developing fetal brain. Epigenetics Chromatin. 2017;10:4.
2. Ladd-Acosta C, Hansen KD, Briem E, Fallin MD, Kaufmann WE, Feinberg AP. Common DNA methylation alterations in multiple brain regions in autism. Mol Psychiatry. 2013;19(8):862–871.
3. Wockner L.F., Morris C.P., Noble E.P., Lawford B.R., Whitehall V.L., Young R.M., Voisey J. Brain-specific epigenetic markers of schizophrenia. Transl. Psychiatry. 2015;5:e680.
4. Lu J, Mccarter M, Lian G, Esposito G, Capoccia E, Delli-Bovi LC, Hecht J, and Sheen V (2016). Global hypermethylation in fetal cortex of Down syndrome due to DNMT3L overexpression. Hum. Mol. Genet. 25, 1714–1727.
5. Rose S, Niyazov DM, Rossignol DA, Goldenthal M, Kahler SG, Frye RE. Clinical and molecular characteristics of mitochondrial dysfunction in autism spectrum disorder. Mol Diagn Ther. (2018) 22:571–93.
6.  Flippo K.H., Strack S. An emerging role for mitochondrial dynamics in schizophrenia. Schizophr. Res. 2017;187:26–32.
7. Helguera P, Seiglie J, Rodriguez J, Hanna M, Helguera G, Busciglio J. Adaptive downregulation of mitochondrial function in down syndrome. Cell Metab. 2013;17(1):132–140.
8. Klymenko Y, Nephew KP. Epigenetic Crosstalk between the Tumor Microenvironment and Ovarian Cancer Cells: A Therapeutic Road Less Traveled. Cancers (Basel). 2018;10(9):295.
9. Eapen V, Crnčec R, Walter A. Clinical outcomes of an early intervention program for preschool children with Autism Spectrum Disorder in a community group setting. BMC Pediatr. 2013;13(1):3.