• R ANJUM Department of Zoology, Government College University, Lahore, Pakistan
  • AU REHMAN Faisalabad Medical University, Allied Hospital Faisalabad, Pakistan
  • H MAQSOOD Faisalabad Medical University, Allied Hospital Faisalabad, Pakistan
  • U ILYAS Faisalabad Medical University, Allied Hospital Faisalabad, Pakistan
  • M NIAZ Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, Pakistan
  • . ROHAIL Department of Zoology, Riphah International University, Faisalabad Campus, Pakistan
  • S MOHSIN Department of Zoology, Government College University, Lahore, Pakistan
  • H JURRAT Department of Zoology, Government College University, Lahore, Pakistan
  • S ANJUM Shaukat Khanum Memorial Cancer Hospital & Research Centre, Pakistan
  • I MUNAWAR Department of Zoology, Riphah International University, Faisalabad Campus, Pakistan
  • M HAMID Registrar, Family Physician, King Saud University Medical City, Riyadh, Saudi Arabia
  • MZ ZAFAR Faisalabad Medical University, Allied Hospital Faisalabad, Pakistan



Epigenetic, Intellectual disability, Malformation syndrome


Intellectual disability (ID) is a condition characterized by defective adaptive and cognitive attitude that can occur with various mental disorders, such as attention deficit/hyperactivity and autism spectrum disorder. It may also be associated with malformation syndromes affecting other organs. Genetic studies have linked several chromatin-modifying enzymes and epigenetic regulators to ID disorders (IDDs). This review explores how dysfunction in histone modifiers, chromatin remodelers, and methyl-DNA binding proteins can cause neurodevelopmental deformities and alter brain plasticity. The use of mouse models generated through human genetics has allowed researchers to uncover the molecular basis of ID and explore potential therapeutic strategies. Understanding the chromatin regulators associated with IDDs has broader implications for treating other IDDs, as they target common downstream genes and cellular functions. Investigating these disorders can also shed light on the function of chromatin regulators in brain growth, plasticity, and gene regulation, leading to new insights into fundamental questions in neurobiology.


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Ambalavanan, N., Carlo, W. A., Shankaran, S., Bann, C. M., Emrich, S. L., Higgins, R. D., ... & Donovan, E. F. (2006). Predicting outcomes of neonates diagnosed with hypoxemic-ischemic encephalopathy. Pediatrics, 118(5), 2084-2093.

American Psychiatric Association. 2000. Diagnostic and statistical manual of mental disorders, Text Revision. 4th ed. Washington: American Psychiatric Association.

Bahari-Javan, S., Maddalena, A., Kerimoglu, C., Wittnam, J., Held, T., Bähr, M., ... & Sananbenesi, F. (2012). HDAC1 regulates fear extinction in mice. Journal of Neuroscience, 32(15), 5062-5073.

Bannister, A. J., & Kouzarides, T. (2011). Regulation of chromatin by histone modifications. Cell research, 21(3), 381.

Benevento, M., van de Molengraft, M., van Westen, R., van Bokhoven, H., & Kasri, N. N. (2015). The role of chromatin repressive marks in cognition and disease: A focus on the repressive complex GLP/G9a. Neurobiology of learning and memory, 124, 88-96.

Bird, A. P. (1980). DNA methylation and the frequency of CpG in animal DNA. Nucleic acids research, 8(7), 1499-1504.

Bird, A., Taggart, M., Frommer, M., Miller, O. J., & Macleod, D. (1985). A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell, 40(1), 91-99.

Bradley, E. A., Thompson, A., & Bryson, S. E. (2002). Mental retardation in teenagers: prevalence data from the Niagara region, Ontario. The Canadian Journal of Psychiatry, 47(7), 652-659.

Cajigas, I. J., Will, T., & Schuman, E. M. (2010). Protein homeostasis and synaptic plasticity. The EMBO journal, 29(16), 2746-2752.

Calis, E. A., Olieman, J. F., Rieken, R., & Penning, C. (2007). Impact of malnutrition on gastrointestinal disorders and gross motor abilities in children with cerebral palsy. Brain and Development, 29(8), 534.

Cao, X., Yeo, G., Muotri, A. R., Kuwabara, T., & Gage, F. H. (2006). Noncoding RNAs in the mammalian central nervous system. Annu. Rev. Neurosci., 29, 77-103.

Carter, S. D., Mifsud, K. R., & Reul, J. M. (2015). Distinct epigenetic and gene expression changes in rat hippocampal neurons after Morris water maze training. Frontiers in behavioral neuroscience, 9, 156.

Castillo-Fernandez, J. E., Spector, T. D., & Bell, J. T. (2014). Epigenetics of discordant monozygotic twins: implications for disease. Genome medicine, 6(7), 60.

Chalei, V., Sansom, S. N., Kong, L., Lee, S., Montiel, J. F., Vance, K. W., & Ponting, C. P. (2014). The long non-coding RNA Dali is an epigenetic regulator of neural differentiation. Elife, 3, e04530.

Chelly, J., Khelfaoui, M., Francis, F., Chérif, B., & Bienvenu, T. (2006). Genetics and pathophysiology of mental retardation. European Journal of Human Genetics, 14(6), 701.

Dawson, M. A., & Kouzarides, T. (2012). Cancer epigenetics: from mechanism to therapy. cell, 150(1), 12-27.

de Groote, M. L., Verschure, P. J., & Rots, M. G. (2012). Epigenetic editing: targeted rewriting of epigenetic marks to modulate expression of selected target genes. Nucleic acids research, 40(21), 10596-10613.

Desmond, M. M., Montgomery, J. R., Melnick, J. L., Cochran, G. G., & Verniaud, W. (1969). Congenital rubella encephalitis: effects on growth and early development. American Journal of Diseases of Children, 118(1), 30-31.

Dierssen, M., Benavides-Piccione, R., Martínez-Cué, C., Estivill, X., Flórez, J., Elston, G. N., & DeFelipe, J. (2003). Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: effects of environmental enrichment. Cerebral cortex, 13(7), 758-764.

Drews, C. D., Yeargin-Allsopp, M., Decoufle, P., & Murphy, C. C. (1995). Variation in the influence of selected sociodemographic risk factors for mental retardation. American journal of public health, 85(3), 329-334.

Durkin, M. (2002). The epidemiology of developmental disabilities in low‐income countries. Mental retardation and developmental disabilities research reviews, 8(3), 206-211.

Emerson, E. (2007). Poverty and people with intellectual disabilities. Mental retardation and developmental disabilities research reviews, 13(2), 107-113.

Emerson, E., & Hatton, C. (2007). Contribution of socioeconomic position to health inequalities of British children and adolescents with intellectual disabilities. American Journal on Mental Retardation, 112(2), 140-150.

Feanny, S. J., Chuang, S. H., Becker, L. E., & Clarke, J. T. R. (1987). Intracerebral paraventricular hyperdensities: a new CT sign in Krabbe globoid cell leukodystrophy. Journal of inherited metabolic disease, 10(1), 24-27.

Feng, J., Chang, H., Li, E., & Fan, G. (2005). Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. Journal of neuroscience research, 79(6), 734-746.

Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., & Tsai, L. H. (2007). Recovery of learning and memory is associated with chromatin remodelling. Nature, 447(7141), 178.

Gilad, R., Lampl, Y., Blumstein, G., & Dan, M. (2007). Neurosyphilis: the reemergence of an historical disease. IMAJ-RAMAT GAN-, 9(2), 117.

Grilli, M., Zappettini, S., Zanardi, A., Lagomarsino, F., Pittaluga, A., Zoli, M., & Marchi, M. (2009). Exposure to an enriched environment selectively increases the functional response of the presynaptic NMDA receptors which modulate noradrenaline release in mouse hippocampus. Journal of Neurochemistry, no-no.

Guan, J. S., Haggarty, S. J., Giacometti, E., Dannenberg, J. H., Joseph, N., Gao, J., ... & Bradner, J. E. (2009). HDAC2 negatively regulates memory formation and synaptic plasticity. Nature, 459(7243), 55.

Guo, J. U., Su, Y., Zhong, C., Ming, G. L., & Song, H. (2011). Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell, 145(3), 423-434.

Gupta, S., Kim, S. Y., Artis, S., Molfese, D. L., Schumacher, A., Sweatt, J. D., ... & Lubin, F. D. (2010). Histone methylation regulates memory formation. Journal of Neuroscience, 30(10), 3589-3599.

Gupta-Agarwal, S., Franklin, A. V., DeRamus, T., Wheelock, M., Davis, R. L., McMahon, L. L., & Lubin, F. D. (2012). G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. Journal of Neuroscience, 32(16), 5440-5453.

Heyward, F. D., & Sweatt, J. D. (2015). DNA methylation in memory formation: emerging insights. The Neuroscientist, 21(5), 475-489.

Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., ... & Zhang, Y. (2011). Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science, 333(6047), 1300-1303.

Jauregi, J., Arias, C., Vegas, O., Alen, F., Martinez, S., Copet, P., & Thuilleaux, D. (2007). A neuropsychological assessment of frontal cognitive functions in Prader–Willi syndrome. Journal of Intellectual Disability Research, 51(5), 350-365.

Kaas, G. A., Zhong, C., Eason, D. E., Ross, D. L., Vachhani, R. V., Ming, G. L., ... & Sweatt, J. D. (2013). TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron, 79(6), 1086-1093.

Katusic, S. K., Colligan, R. C., Beard, C. M., O'Fallon, W. M., Bergstralh, E. J., Jacobsen, S. J., & Kurland, L. T. (1996). Mental retardation in a birth cohort, 1976-1980, Rochester, Minnesota. American journal of mental retardation: AJMR, 100(4), 335-344.

Kerimoglu, C., Agis-Balboa, R. C., Kranz, A., Stilling, R., Bahari-Javan, S., Benito-Garagorri, E., ... & Fischer, A. (2013). Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. Journal of Neuroscience, 33(8), 3452-3464.

Kim, M. S., Akhtar, M. W., Adachi, M., Mahgoub, M., Bassel-Duby, R., Kavalali, E. T., ... & Monteggia, L. M. (2012). An essential role for histone deacetylase 4 in synaptic plasticity and memory formation. Journal of Neuroscience, 32(32), 10879-10886.

Kodituwakku, P. W. (2007). Defining the behavioral phenotype in children with fetal alcohol spectrum disorders: a review. Neuroscience & Biobehavioral Reviews, 31(2), 192-201.

Korzus, E., Rosenfeld, M. G., & Mayford, M. (2004). CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron, 42(6), 961-972.

Leonard, H., & Wen, X. (2002). The epidemiology of mental retardation: challenges and opportunities in the new millennium. Mental retardation and developmental disabilities research reviews, 8(3), 117-134.

Leonard, H., de Klerk, N., Bourke, J., & Bower, C. (2006). Maternal health in pregnancy and intellectual disability in the offspring: a population-based study. Annals of epidemiology, 16(6), 448-454.

Leonard, H., Petterson, B., De Klerk, N., Zubrick, S. R., Glasson, E., Sanders, R., & Bower, C. (2005). Association of sociodemographic characteristics of children with intellectual disability in Western Australia. Social science & medicine, 60(7), 1499-1513.

Levenson, J. M., O'Riordan, K. J., Brown, K. D., Trinh, M. A., Molfese, D. L., & Sweatt, J. D. (2004). Regulation of histone acetylation during memory formation in the hippocampus. Journal of Biological Chemistry, 279(39), 40545-40559.

Lin, N., Chang, K. Y., Li, Z., Gates, K., Rana, Z. A., Dang, J., ... & Head, S. R. (2014). An evolutionarily conserved long noncoding RNA TUNA controls pluripotency and neural lineage commitment. Molecular cell, 53(6), 1005-1019.

Lister, R., Mukamel, E. A., Nery, J. R., Urich, M., Puddifoot, C. A., Johnson, N. D., ... & Yu, M. (2013). Global epigenomic reconfiguration during mammalian brain development. Science, 341(6146), 1237905.

Lopez-Atalaya, J. P., & Barco, A. (2014). Can changes in histone acetylation contribute to memory formation?. Trends in Genetics, 30(12), 529-539.

Lopez-Atalaya, J. P., Ito, S., Valor, L. M., Benito, E., & Barco, A. (2013). Genomic targets, and histone acetylation and gene expression profiling of neural HDAC inhibition. Nucleic acids research, 41(17), 8072-8084.

Lubin, F. D., Gupta, S., Parrish, R. R., Grissom, N. M., & Davis, R. L. (2011). Epigenetic mechanisms: critical contributors to long-term memory formation. The Neuroscientist, 17(6), 616-632.

Lubin, F. D., Roth, T. L., & Sweatt, J. D. (2008). Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. Journal of Neuroscience, 28(42), 10576-10586.

Matson, J. L., Dixon, D. R., Matson, M. L., & Logan, J. R. (2005). Classifying mental retardation and specific strength and deficit areas in severe and profoundly mentally retarded persons with the MESSIER. Research in developmental disabilities, 26(1), 41-45.

McLaren, J., & Bryson, S. E. (1987). Review of recent epidemiological studies of mental retardation: prevalence, associated disorders, and etiology. American Journal on Mental Retardation.

McLaren, J., & Bryson, S. E. (1987). Review of recent epidemiological studies of mental retardation: prevalence, associated disorders, and etiology. American Journal on Mental Retardation.

McQuown, S. C., Barrett, R. M., Matheos, D. P., Post, R. J., Rogge, G. A., Alenghat, T., ... & Wood, M. A. (2011). HDAC3 is a critical negative regulator of long-term memory formation. Journal of Neuroscience, 31(2), 764-774.

Michán, S., Li, Y., Chou, M. M. H., Parrella, E., Ge, H., Long, J. M., ... & Mervis, R. F. (2010). SIRT1 is essential for normal cognitive function and synaptic plasticity. Journal of Neuroscience, 30(29), 9695-9707.

Miller, C. A., & Sweatt, J. D. (2007). Covalent modification of DNA regulates memory formation. Neuron, 53(6), 857-869.

Miller, C. A., Gavin, C. F., White, J. A., Parrish, R. R., Honasoge, A., Yancey, C. R., ... & Sweatt, J. D. (2010). Cortical DNA methylation maintains remote memory. Nature neuroscience, 13(6), 664.

Morrow, C. E., Culbertson, J. L., Accornero, V. H., Xue, L., Anthony, J. C., & Bandstra, E. S. (2006). Learning disabilities and intellectual functioning in school-aged children with prenatal cocaine exposure. Developmental neuropsychology, 30(3), 905-931.

Mouridsen, S. E., & Sørensen, S. A. (1995). Psychological aspects of von Recklinghausen neurofibromatosis (NF1). Journal of medical genetics, 32(12), 921-924.

Naeye, R. L. (1978). Placenta previa. Predisposing factors and effects on the fetus and surviving infants. Obstetrics and gynecology, 52(5), 521-525.

Nan, X., Meehan, R. R., & Bird, A. (1993). Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic acids research, 21(21), 4886-4892.

Nebbioso, A., Carafa, V., Benedetti, R., & Altucci, L. (2012). Trials with ‘epigenetic’drugs: an update. Molecular oncology, 6(6), 657-682.

Niswander, K. R., Gordon, M., & Drage, J. S. (1975). The effect of intrauterine hypoxia on the child surviving to 4 years. American journal of obstetrics and gynecology, 121(7), 892-899.

Nithianantharajah, J., & Hannan, A. J. (2006). Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nature Reviews Neuroscience, 7(9), 697.

Noyola, D.E., Demmler, G.J., Nelson, C.T., Griesser, C., Williamson, W.D., Atkins, J.T., Rozelle, J., Turcich, M., Llorente, A.M., Sellers-Vinson, S. and Reynolds, A., (2001). Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection. The Journal of pediatrics, 138(3), 325-331.

Nyhan, W. L., Wulfeck, B. B., Tallal, P., & Marsden, D. L. (1989). Metabolic correlates of learning disability. Birth defects original article series, 25(6), 153-169.

Okano, M., Bell, D. W., Haber, D. A., & Li, E. (1999). DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell, 99(3), 247-257.

Olave, I., Wang, W., Xue, Y., Kuo, A., & Crabtree, G. R. (2002). Identification of a polymorphic, neuron-specific chromatin remodeling complex. Genes & development, 16(19), 2509-2517.

Papi, A., Ferreri, A. M., Rocchi, P., Guerra, F., & Orlandi, M. (2010). Epigenetic modifiers as anticancer drugs: effectiveness of valproic acid in neural crest-derived tumor cells. Anticancer research, 30(2), 535-540.

Rauch, A., Hoyer, J., Guth, S., Zweier, C., Kraus, C., Becker, C., Zenker, M., Hüffmeier, U., Thiel, C., Rüschendorf, F. and Nürnberg, P., 2006. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. American journal of medical genetics Part A, 140(19), pp.2063-2074.

Roeleveld, N., Zielhuis, G. A. and Gabreels, F. (1997). The prevalence of mental retardation: a critical review of recent literature. Developmental Medicine & Child Neurology, 39(2), 125-132.

Ropers, H. H. (2006). X-linked mental retardation: many genes for a complex disorder. Current opinion in genetics & development, 16(3), 260-269.

Ropers, H. H., & Hamel, B. C. (2005). X-linked mental retardation. Nature reviews genetics, 6(1), 46.

Rudenko, A., Dawlaty, M. M., Seo, J., Cheng, A. W., Meng, J., Le, T., ... & Tsai, L. H. (2013). Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron, 79(6), 1109-1122.

Schaefer, A., Sampath, S. C., Intrator, A., Min, A., Gertler, T. S., Surmeier, D. J., ... & Greengard, P. (2009). Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron, 64(5), 678-691.

Schaefer, T. L., Davenport, M. H., & Erickson, C. A. (2015). Emerging pharmacologic treatment options for fragile X syndrome. The application of clinical genetics, 8, 75.

Scheller, J. M., & Nelson, K. B. (1994). Does cesarean delivery prevent cerebral palsy or other neurologic problems of childhood?. Obstetrics and gynecology, 83(4), 624-630.

Selman, V., Selman, R. C., Selman, J., & Selman, E. (2005). Spiritual-intelligence/-quotient. College Teaching Methods & Styles Journal, 1(3), 23-30.

Seppänen, M., Meri, S., Notkola, I. L., Seppälä, I. J., Hiltunen-Back, E., Sarvas, H., ... & Lokki, M. L. (2006). Subtly impaired humoral immunity predisposes to frequently recurring genital herpes simplex virus type 2 infection and herpetic neuralgia. The Journal of infectious diseases, 194(5), 571-578.

Shin, J., Ming, G. L., & Song, H. (2015). Seeking a roadmap toward neuroepigenetics. Neuron, 86(1), 12-15.

Shin, S. S., Bales, J. W., Yan, H. Q., Kline, A. E., Wagner, A. K., Lyons-Weiler, J., & Dixon, C. E. (2013). The effect of environmental enrichment on substantia nigra gene expression after traumatic brain injury in rats. Journal of neurotrauma, 30(4), 259-270.

Siitonen, S. L., Kauppinen, T., Leino, T. K., Vanninen, E., Kuronen, P., & Länsimies, E. (2003). Cerebral blood flow during acceleration in flight measured with SPECT. Aviation, space, and environmental medicine, 74(3), 201-206.

Song, C. X., Szulwach, K. E., Fu, Y., Dai, Q., Yi, C., Li, X., ... & Wang, J. (2011). Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nature biotechnology, 29(1), 68.

Téllez-Rojo, M. M., Bellinger, D. C., Arroyo-Quiroz, C., Lamadrid-Figueroa, H., Mercado-Garcia, A., Schnaas-Arrieta, L., ... & Hu, H. (2006). Longitudinal associations between blood lead concentrations lower than 10 μg/dL and neurobehavioral development in environmentally exposed children in Mexico City. Pediatrics, 118(2), e323-e330.

Tsankova, N. M., Berton, O., Renthal, W., Kumar, A., Neve, R. L., & Nestler, E. J. (2006). Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature neuroscience, 9(4), 519.

Vaissière, T., Sawan, C., & Herceg, Z. (2008). Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutation Research/Reviews in Mutation Research, 659(1-2), 40-48.

Varley, K. E., Gertz, J., Bowling, K. M., Parker, S. L., Reddy, T. E., Pauli-Behn, F., ... & Absher, D. M. (2013). Dynamic DNA methylation across diverse human cell lines and tissues. Genome research, 23(3), 555-567.

Vogel-Ciernia, A., Matheos, D. P., Barrett, R. M., Kramár, E. A., Azzawi, S., Chen, Y., ... & Jia, Y. (2013). The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory. Nature neuroscience, 16(5), 552.

Waddington, C. H. (1956). Genetic assimilation of the bithorax phenotype. Evolution, 10(1), 1-13.

Weaving, L. S., Ellaway, C. J., Gecz, J., & Christodoulou, J. (2005). Rett syndrome: clinical review and genetic update. Journal of medical genetics, 42(1), 1-7.

Wiltgen, B. J., Brown, R. A., Talton, L. E., & Silva, A. J. (2004). New circuits for old memories: the role of the neocortex in consolidation. Neuron, 44(1), 101-108.

Zahir, F., & Friedman, J. M. (2007). The impact of array genomic hybridization on mental retardation research: a review of current technologies and their clinical utility. Clinical genetics, 72(4), 271-287.

Gorgoni, M., Scarpelli, S., Reda, F., & De Gennaro, L. (2020). Sleep EEG oscillations in neurodevelopmental disorders without intellectual disabilities. Sleep Medicine Reviews, 49, 101224.

Maulik, P. K., Mascarenhas, M. N., Mathers, C. D., Dua, T., & Saxena, S. (2011). Prevalence of intellectual disability: a meta-analysis of population-based studies. Research in developmental disabilities, 32(2), 419-436.

Luckasson, R., & Schalock, R. L. (2013). Defining and applying a functionality approach to intellectual disability. Journal of Intellectual Disability Research, 57(7), 657-668.

Miclea, D., Peca, L., Cuzmici, Z., & Pop, I. V. (2015). Genetic testing in patients with global developmental delay/intellectual disabilities. A review. Clujul Medical, 88(3), 288.

Curatolo, P., Moavero, R., Roberto, D., & Graziola, F. (2015, December). Genotype/phenotype correlations in tuberous sclerosis complex. In Seminars in pediatric neurology (Vol. 22, No. 4, pp. 259-273). WB Saunders.

Tomita, T., Mukhopadhyay, D., Han, B., Yakubu, R., Tu, V., Mayoral, J., ... & Weiss, L. M. (2021). Toxoplasma gondii matrix antigen 1 is a secreted immunomodulatory effector. Mbio, 12(3), e00603-21.




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