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Intellectual disability in children: Evaluation for a cause

Penelope Pivalizza, MD
Seema R Lalani, MD
Section Editors
Marc C Patterson, MD, FRACP
Helen V Firth, DM, FRCP, DCH
Carolyn Bridgemohan, MD
Deputy Editor
Carrie Armsby, MD, MPH


Intellectual disability (ID) is a neurodevelopmental disorder with multiple etiologies that is characterized by deficits in intellectual and adaptive functioning presenting before 18 years of age. ID encompasses a broad spectrum of functioning, disability, and strengths [1]. ID is an important public health issue because of its prevalence and the need for extensive support services. Its management requires early diagnosis and intervention, coupled with access to health care and appropriate supports. Identifying a cause enables focused interventions, treatments, surveillance, and appropriate counseling, with anticipation of possible medical or behavioral complications and a more specific prognosis [2].

This topic reviews the epidemiology of ID and the evaluation of affected children for a specific cause. Other aspects of ID are discussed separately:

(See "Intellectual disability in children: Definition, diagnosis, and assessment of needs".)

(See "Intellectual disability in children: Management, outcomes, and prevention".)


The following terms are used throughout this topic (see "Intellectual disability in children: Definition, diagnosis, and assessment of needs", section on 'Definitions'):

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Literature review current through: Nov 2017. | This topic last updated: May 26, 2016.
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  1. American Psychiatric Association. Intellectual Disability (Intellectual Developmental Disorder). In: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, American Psychiatric Association (Ed), Arlington, VA 2013. p.33.
  2. Moeschler JB, Shevell M, Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics 2014; 134:e903.
  3. Szymanski L, King BH. Practice parameters for the assessment and treatment of children, adolescents, and adults with mental retardation and comorbid mental disorders. American Academy of Child and Adolescent Psychiatry Working Group on Quality Issues. J Am Acad Child Adolesc Psychiatry 1999; 38:5S.
  4. Szymanski L, King BH. Summary of the Practice Parameters for the Assessment and Treatment of Children, Adolescents, and Adults with Mental Retardation and Comorbid Mental Disorders. American Academy of Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry 1999; 38:1606.
  5. Harris JC. The classification of intellectual disability. In: Intellectual disability: Understanding its development, causes, classification, evaluation, and treatment, Oxford University Press, New York 2006. p.42.
  6. Veltman JA, Brunner HG. De novo mutations in human genetic disease. Nat Rev Genet 2012; 13:565.
  7. Maulik PK, Mascarenhas MN, Mathers CD, et al. Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil 2011; 32:419.
  8. Moeschler JB, Shevell M, American Academy of Pediatrics Committee on Genetics. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics 2006; 117:2304.
  9. Shevell M, Ashwal S, Donley D, et al. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology 2003; 60:367.
  10. Ramer JC, Miller G. Overview of Mental Retardation. In: Static Encephalopathies of Infancy and Childhood, Miller G, Ramer JC (Eds), Raven Press, New York 1992.
  11. McLaren J, Bryson SE. Review of recent epidemiological studies of mental retardation: prevalence, associated disorders, and etiology. Am J Ment Retard 1987; 92:243.
  12. Kaufman L, Ayub M, Vincent JB. The genetic basis of non-syndromic intellectual disability: a review. J Neurodev Disord 2010; 2:182.
  13. Chiurazzi P, Pirozzi F. Advances in understanding - genetic basis of intellectual disability. F1000Res 2016; 5.
  14. Croen LA, Grether JK, Selvin S. The epidemiology of mental retardation of unknown cause. Pediatrics 2001; 107:E86.
  15. Chapman DA, Scott KG, Mason CA. Early risk factors for mental retardation: role of maternal age and maternal education. Am J Ment Retard 2002; 107:46.
  16. Leonard H, Glasson E, Nassar N, et al. Autism and intellectual disability are differentially related to sociodemographic background at birth. PLoS One 2011; 6:e17875.
  17. Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 2012; 380:1674.
  18. Moeschler JB. Genetic evaluation of intellectual disabilities. Semin Pediatr Neurol 2008; 15:2.
  19. Leonard H, Wen X. The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev 2002; 8:117.
  20. van Karnebeek CD, Scheper FY, Abeling NG, et al. Etiology of mental retardation in children referred to a tertiary care center: a prospective study. Am J Ment Retard 2005; 110:253.
  21. Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 2015; 519:223.
  22. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86:749.
  23. Engbers HM, Berger R, van Hasselt P, et al. Yield of additional metabolic studies in neurodevelopmental disorders. Ann Neurol 2008; 64:212.
  24. van Karnebeek CD, Shevell M, Zschocke J, et al. The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab 2014; 111:428.
  25. Chelly J, Khelfaoui M, Francis F, et al. Genetics and pathophysiology of mental retardation. Eur J Hum Genet 2006; 14:701.
  26. Chiurazzi P, Oostra BA. Genetics of mental retardation. Curr Opin Pediatr 2000; 12:529.
  27. Rauch A, Hoyer J, Guth S, et al. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet A 2006; 140:2063.
  28. Merla G, Brunetti-Pierri N, Micale L, Fusco C. Copy number variants at Williams-Beuren syndrome 7q11.23 region. Hum Genet 2010; 128:3.
  29. Elsea SH, Girirajan S. Smith-Magenis syndrome. Eur J Hum Genet 2008; 16:412.
  30. Buiting K. Prader-Willi syndrome and Angelman syndrome. Am J Med Genet C Semin Med Genet 2010; 154C:365.
  31. de Ligt J, Willemsen MH, van Bon BW, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012; 367:1921.
  32. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013; 369:1502.
  33. Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014; 312:1870.
  34. Monroe GR, Frederix GW, Savelberg SM, et al. Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability. Genet Med 2016; 18:949.
  35. Kilic E, Cetinkaya A, Utine GE, Boduroğlu K. A Diagnosis to Consider in Intellectual Disability: Mowat-Wilson Syndrome. J Child Neurol 2016; 31:913.
  36. van Karnebeek CD, Jansweijer MC, Leenders AG, et al. Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet 2005; 13:6.
  37. Molinari F, Rio M, Meskenaite V, et al. Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation. Science 2002; 298:1779.
  38. Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP. A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology 2004; 63:1927.
  39. Basel-Vanagaite L, Attia R, Yahav M, et al. The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation. J Med Genet 2006; 43:203.
  40. Garshasbi M, Hadavi V, Habibi H, et al. A defect in the TUSC3 gene is associated with autosomal recessive mental retardation. Am J Hum Genet 2008; 82:1158.
  41. Motazacker MM, Rost BR, Hucho T, et al. A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation. Am J Hum Genet 2007; 81:792.
  42. Mir A, Kaufman L, Noor A, et al. Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation. Am J Hum Genet 2009; 85:909.
  43. Hu H, Eggers K, Chen W, et al. ST3GAL3 mutations impair the development of higher cognitive functions. Am J Hum Genet 2011; 89:407.
  44. Pak C, Garshasbi M, Kahrizi K, et al. Mutation of the conserved polyadenosine RNA binding protein, ZC3H14/dNab2, impairs neural function in Drosophila and humans. Proc Natl Acad Sci U S A 2011; 108:12390.
  45. Ropers HH. Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet 2010; 11:161.
  46. Stevenson RE, Charles E, Schwartz R, Rogers RC. Atlas of X-Linked Intellectual Disability Syndromes, Oxford University Press, New York 2012.
  47. Michelson DJ, Shevell MI, Sherr EH, et al. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2011; 77:1629.
  48. Lugtenberg D, Kleefstra T, Oudakker AR, et al. Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy. Eur J Hum Genet 2009; 17:444.
  49. Grasshoff U, Bonin M, Goehring I, et al. De novo MECP2 duplication in two females with random X-inactivation and moderate mental retardation. Eur J Hum Genet 2011; 19:507.
  50. Scott Schwoerer J, Laffin J, Haun J, et al. MECP2 duplication: possible cause of severe phenotype in females. Am J Med Genet A 2014; 164A:1029.
  51. van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, et al. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet 2013; 50:463.
  52. Hoffman-Zacharska D, Mierzewska H, Szczepanik E, et al. The spectrum of PLP1 gene mutations in patients with the classical form of the Pelizaeus-Merzbacher disease. Med Wieku Rozwoj 2013; 17:293.
  53. Hoffman-Zacharska D, Kmieć T, Poznański J, et al. Mutations in the PLP1 gene residue p. Gly198 as the molecular basis of Pelizeaus-Merzbacher phenotype. Brain Dev 2013; 35:877.
  54. Wong LJ. Molecular genetics of mitochondrial disorders. Dev Disabil Res Rev 2010; 16:154.
  55. Huang J, Zhu T, Qu Y, Mu D. Prenatal, Perinatal and Neonatal Risk Factors for Intellectual Disability: A Systemic Review and Meta-Analysis. PLoS One 2016; 11:e0153655.
  56. Jarjour IT. Neurodevelopmental outcome after extreme prematurity: a review of the literature. Pediatr Neurol 2015; 52:143.
  57. McDonald L, Rennie A, Tolmie J, et al. Investigation of global developmental delay. Arch Dis Child 2006; 91:701.
  58. Shevell MI, Majnemer A, Rosenbaum P, Abrahamowicz M. Etiologic yield of subspecialists' evaluation of young children with global developmental delay. J Pediatr 2000; 136:593.
  59. al-Qudah AA. Screening for congenital hypothyroidism in cognitively delayed children. Ann Trop Paediatr 1998; 18:285.
  60. Essex C, Roper H. Lesson of the week: late diagnosis of Duchenne's muscular dystrophy presenting as global developmental delay. BMJ 2001; 323:37.
  61. Ciafaloni E, Fox DJ, Pandya S, et al. Delayed diagnosis in duchenne muscular dystrophy: data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). J Pediatr 2009; 155:380.
  62. Firth HV, Richards SM, Bevan AP, et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet 2009; 84:524.
  63. Sagoo GS, Butterworth AS, Sanderson S, et al. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genet Med 2009; 11:139.
  64. Moeschler JB. Medical genetics diagnostic evaluation of the child with global developmental delay or intellectual disability. Curr Opin Neurol 2008; 21:117.
  65. Oostlander AE, Meijer GA, Ylstra B. Microarray-based comparative genomic hybridization and its applications in human genetics. Clin Genet 2004; 66:488.
  66. Ropers HH. Genetics of intellectual disability. Curr Opin Genet Dev 2008; 18:241.
  67. Hochstenbach R, van Binsbergen E, Engelen J, et al. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. Eur J Med Genet 2009; 52:161.
  68. Boone PM, Bacino CA, Shaw CA, et al. Detection of clinically relevant exonic copy-number changes by array CGH. Hum Mutat 2010; 31:1326.
  69. Wiszniewski W, Hunter JV, Hanchard NA, et al. TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities. Am J Hum Genet 2013; 93:197.
  70. Conlin LK, Thiel BD, Bonnemann CG, et al. Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Hum Mol Genet 2010; 19:1263.
  71. Wiszniewska J, Bi W, Shaw C, et al. Combined array CGH plus SNP genome analyses in a single assay for optimized clinical testing. Eur J Hum Genet 2014; 22:79.
  72. Paciorkowski AR, Fang M. Chromosomal microarray interpretation: what is a child neurologist to do? Pediatr Neurol 2009; 41:391.
  73. Hersh JH, Saul RA, Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics 2011; 127:994.
  74. Hall SS, Lightbody AA, Reiss AL. Compulsive, self-injurious, and autistic behavior in children and adolescents with fragile X syndrome. Am J Ment Retard 2008; 113:44.
  75. American College of Medical Genetics and Genomics (ACMG) Policy Statement: Points to Consider in the Clinical Application of Genomic Sequencing. Available at: https://www.acmg.net/StaticContent/PPG/Clinical_Application_of_Genomic_Sequencing.pdf (Accessed on May 03, 2016).
  76. Johansen Taber KA, Dickinson BD, Wilson M. The promise and challenges of next-generation genome sequencing for clinical care. JAMA Intern Med 2014; 174:275.
  77. De Vries BB, Winter R, Schinzel A, van Ravenswaaij-Arts C. Telomeres: a diagnosis at the end of the chromosomes. J Med Genet 2003; 40:385.
  78. Lewendon G, Kinra S, Nelder R, Cronin T. Should children with developmental and behavioural problems be routinely screened for lead? Arch Dis Child 2001; 85:286.
  79. CDC response to Advisory Committee on Childhood Lead Poisoning Prevention Recommendations in "Low Level Lead Exposure Harms Children: A Renewed Call of Primary Prevention" http://www.cdc.gov/nceh/lead/ACCLPP/activities.htm (Accessed on May 17, 2012).
  80. Majnemer A, Shevell MI. Diagnostic yield of the neurologic assessment of the developmentally delayed child. J Pediatr 1995; 127:193.
  81. Demaerel P, Kingsley DP, Kendall BE. Isolated neurodevelopmental delay in childhood: clinicoradiological correlation in 170 patients. Pediatr Radiol 1993; 23:29.
  82. Bouhadiba Z, Dacher J, Monroc M, et al. [MRI of the brain in the evaluation of children with developmental delay]. J Radiol 2000; 81:870.
  83. Decobert F, Grabar S, Merzoug V, et al. Unexplained mental retardation: is brain MRI useful? Pediatr Radiol 2005; 35:587.
  84. Battaglia A, Bianchini E, Carey JC. Diagnostic yield of the comprehensive assessment of developmental delay/mental retardation in an institute of child neuropsychiatry. Am J Med Genet 1999; 82:60.