Molecular Genetics of Mental Retardation

Abstract

Mental retardation (MR) affects 1–3% of the population. It can be subdivided into syndromic and nonsyndromic forms. The empiric recurrence risk for siblings in families with a mentally retarded child is 8–10%. Gross chromosomal imbalances are implicated in the aetiology in 10–24% of cases and cryptic chromosomal imbalances in about 10%. In families with X‐linked MR (XLMR) a disease‐causing mutation can be identified in 42%; in families with autosomal recessive MR a causative mutation can be identified only rarely since only five genes have been discovered. The function of many of the proteins involved in MR is related to signal transduction, regulation of transcription, core metabolism, DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) processing, protein synthesis, regulation of cell cycle or ubiquitination. Establishing a molecular diagnosis in mentally retarded individuals can have a major impact on reproductive counselling, prevention of mental handicap and on further understanding of molecular mechanisms involved in human cognitive processes.

Key concepts

  • Mental retardation can be subdivided into syndromic forms, characterized by cognitive impairment accompanied by dysmorphic features, malformations or neurological abnormalities, and nonsyndromic forms, characterized by MR without additional features.

  • Gross chromosomal imbalances can be identified in 10–24% of the patients with MR and are more frequently found in patients with syndromic MR.

  • Pathogenic cryptic copy number changes are implicated in the aetiology of ∼10% of cases of all types of MR; the frequency of cryptic chromosomal imbalances is unknown in nonsyndromic MR.

  • Culturo‐familial MR is believed to be caused by a combination of genetic and environmental factors and is usually nonsyndromic; possible quantitative trait loci that play a role in the predisposition to MR have been identified.

  • More than 80 genes are known to be involved in nonsyndromic and syndromic XLMR. After exclusion of Fragile X syndrome, mutations in these genes can be identified in 42% of individuals with XLMR.

  • Only five genes and eight loci are known to be involved in autosomal recessive nonsyndromic MR, and most of the causative genes still have to be discovered.

  • The functions of proteins involved in cognitive impairment are diverse and are related to signal transduction, regulation of transcription, core metabolism, DNA and RNA processing, protein synthesis, regulation of the cell cycle, ubiquitination and other cellular processes.

  • Diagnostic workup of patients with MR should include all or some of the following: careful dysmorphological and neurological examination, karyotyping, fragile X analysis, investigations aimed at detection of microdeletions/microduplications and resequencing of mental retardation‐causing genes. Mutations in some of the genes can be suspected due to the existence of specific metabolic or endocrine abnormalities.

  • Empiric recurrence risks for siblings in families with a mentally retarded child are 8–10%. Recurrence risks for MR caused by single gene mutations depend on the mode of inheritance.

  • A large‐scale programme for the prevention of MR based on carrier screening is rarely possible in specific populations except for Fragile X syndrome. Prenatal diagnostic options in most of the at‐risk families are not available since the chances of identifying a mutation in a proband with unexplained MR are still low.

Keywords: mental retardation; syndromic; nonsyndromic; chromosomal aberrations; monogenic causes

Figure 1.

Ideogram of the X‐chromosome with the positions of the 82 known XLMR genes. Genes written in black cause syndromes, those written in grey preceded by a + sign cause neuromuscular disorders, whereas those in grey preceded by an asterisk are involved in nonspecific (MRX) conditions. Reprinted by permission from Macmillan Publishers Ltd Chiurazzi et al., copyright (2008).

Figure 2.

Pie charts illustrating (a) subcellular localization and (b) the molecular function of proteins encoded by the 82 known XLMR genes, according to the available Gene Onthology annotations (www.geneontology.org). Reprinted by permission from Macmillan Publishers Ltd Chiurazzi et al..

close

References

American Psychiatric Association. (1994) Disorders usually first diagnosed in infancy, childhood, or adolescence. In: DSM‐IV, Diagnostic Criteria, pp. 39–46. Washington, DC: APA.

Basel‐Vanagaite L, Attia R, Yahav M et al. (2006) The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non‐syndromic mental retardation. Journal of Medical Genetics 43: 203–210.

Basel‐Vanagaite L, Taub E, Halpern GJ et al. (2007) Genetic screening for autosomal recessive nonsyndromic mental retardation in an isolated population in Israel. European Journal of Human Genetics 15: 250–253.

de Brouwer AP, Yntema HG, Kleefstra T et al. (2007) Mutation frequencies of X‐linked mental retardation genes in families from the EuroMRX consortium. Human Mutation 28: 207–208.

Butcher LM, Meaburn E, Dale PS et al. (2005a) Association analysis of mild mental impairment using DNA pooling to screen 432 brain‐expressed single‐nucleotide polymorphisms. Molecular Psychiatry 10: 384–392.

Butcher LM, Meaburn E, Knight J et al. (2005b) SNPs, microarrays and pooled DNA: identification of four loci associated with mild mental impairment in a sample of 6000 children. Human Molecular Genetics 14: 1315–1325.

Chen W, Jensen LR, Gecz J et al. (2007) Mutation screening of brain‐expressed X‐chromosomal miRNA genes in 464 patients with nonsyndromic X‐linked mental retardation. European Journal of Human Genetics 15: 375–378.

Chiurazzi P, Schwartz CE, Gecz J and Neri G (2008) XLMR genes: update 2007. European Journal of Human Genetics 16: 422–434.

Curry CJ, Sandhu A, Frutos L and Wells R (1996) Diagnostic yield of genetic evaluations in developmental delay/mental retardation. Clinical Research 44: 130A.

Curry CJ, Stevenson RE, Aughton D et al. (1997) Evaluation of mental retardation: recommendations of a Consensus Conference: American College of Medical Genetics. American Journal of Medical Genetics 72: 468–477.

Fang JS, Lee KF, Huang CT et al. (2008) Cytogenetic and molecular characterization of a three‐generation family with chromosome 5p terminal deletion. Clinical Genetics 73: 585–590.

Fishburn J, Turner G, Daniel A and Brookwell R (1983) The diagnosis and frequency of X‐linked conditions in a cohort of moderately retarded males with affected brothers. American Journal of Medical Genetics 14: 713–724.

Frints SG, Marynen P, Hartmann D et al. (2003) CALL interrupted in a patient with non‐specific mental retardation: gene dosage‐dependent alteration of murine brain development and behavior. Human Molecular Genetics 12: 1463–1474.

Froyen G, Van Esch H, Bauters M et al. (2007) Detection of genomic copy number changes in patients with idiopathic mental retardation by high‐resolution X‐array‐CGH: important role for increased gene dosage of XLMR genes. Human Mutation 28: 1034–1042.

Garshasbi M, Hadavi V, Habibi H et al. (2008) A defect in the TUSC3 gene is associated with autosomal recessive mental retardation. American Journal of Medical Genetics 82: 1158–1164.

Guzauskas GF, Ukadike K, Rimsky L and Srivastava AK (2007) tSNP‐based identification of allelic loss of gene expression in a patient with a balanced chromosomal rearrangement. Genomics 89: 562–565.

Herbst DS and Miller JR (1980) Nonspecific X‐linked mental retardation II: the frequency in British Columbia. American Journal of Medical Genetics 7: 461–469.

Higgins JJ, Pucilowska J, Lombardi RQ and Rooney JP (2004) A mutation in a novel ATP‐dependent Lon protease gene in a kindred with mild mental retardation. Neurology 63: 1927–1931.

Hunter AG (2000) Outcome of the routine assessment of patients with mental retardation in a genetics clinic. American Journal of Medical Genetics 90: 60–68.

Ji Y, Eichler EE, Schwartz S and Nicholls RD (2000) Structure of chromosomal duplicons and their role in mediating human genomic disorders. Genome Research 10: 597–610.

van Karnebeek CD, Jansweijer MC, Leenders AG, Offringa M and Hennekam RC (2005b) Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. European Journal of Human Genetics 13: 6–25.

van Karnebeek CD, Scheper FY, Abeling NG et al. (2005a) Etiology of mental retardation in children referred to a tertiary care center: a prospective study. American Journal on Mental Retardation 110: 253–267.

Knight S, Regan R, Nicod A et al. (1999) Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 354: 1676–1681.

Koolen DA, Sistermans EA, Nilessen W et al. (2008) Identification of non‐recurrent submicroscopic genome imbalances: the advantage of genome‐wide microarrays over targeted approaches. European Journal of Human Genetics 16: 395–400.

Kuss AW, Abbasi‐Moheb L, Garshasbi M et al. (2007) Autozygosity Mapping in a Large Cohort of Consanguineous Iranian Families Reveals a Frequent Locus for Autosomal Recessive Mental Retardation. Venice: XLMR workshop.

Laumonnier F, Roger S, Guérin P et al. (2006) Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation. American Journal of Psychiatry 163: 1622–1629.

Leonard H and Wen X (2002) The epidemiology of mental retardation: challenges and opportunities in the new millennium. Mental Retardation and Developmental Disabilities Research Reviews 8: 117–134.

Lerer I, Sagi M, Meiner V et al. (2005) Deletion of the ANKRD15 gene at 9p24.3 causes parent‐of‐origin‐dependent inheritance of familial cerebral palsy. Human Molecular Genetics 14: 3911–3920.

Lugtenberg D, Hamel BJC, van Bokhoven H and de Brouwer A (2006) Strategies for present and future mental retardation diagnosis. Future Neurology 1: 775–785.

Macayran JF, Cederbaum SD and Fox MA (2006) Diagnostic yield of chromosome analysis in patients with developmental delay or mental retardation who are otherwise nondysmorphic. American Journal of Medical Genetics A 140: 2320–2323.

Mandel JL and Chelly J (2004) Monogenic X‐linked mental retardation: is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations. European Journal of Human Genetics 12: 689–693.

Molinari F, Foulquier F, Tarpey PS et al. (2008) Oligosaccharyltransferase‐subunit mutations in nonsyndromic mental retardation. American Journal of Human Genetics 82: 1150–1157.

Molinari F, Rio M, Meskenaite V et al. (2002) Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation. Science 298(5599): 1779–1781.

Motazacker MM, Rost BR, Hucho T et al. (2007) A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation. American Journal of Human Genetics 81: 792–798.

Najmabadi H, Motazacker MM, Garshasbi M et al. (2007) Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non‐syndromic autosomal recessive mental retardation and identifies 8 novel gene loci. Human Genetics 121: 43–48.

Nicholls RD, Knoll JH, Butler MG, Karam S and Lalande M (1989) Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader‐Willi syndrome. Nature 342(6247): 281–285.

Pinkel D, Segraves R, Sudar D et al. (1998) High‐resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nature Genetics 20: 207–211.

Plenge RM, Stevenson RA, Lubs HA, Schwartz CE and Willard HF (2002) Skewed X‐chromosome inactivation is a common feature of X‐linked mental retardation disorders. American Journal of Human Genetics 71: 168–173.

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

Ropers HH (2007) New perspectives for the elucidation of genetic disorders. American Journal of Human Genetics 81: 199–207.

Sebat J, Lakshmi B, Troge J et al. (2004) Large‐scale copy number polymorphism in the human genome. Science 305(5683): 525–528.

Spinath FM, Harlaar N, Ronald A and Plomin R (2004) Substantial genetic influence on mild mental impairment in early childhood. American Journal on Mental Retardation 109: 34–43.

Stankiewitz P and Beaudet AL (2007) Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Current Opinion in Genetics and Development 17: 182–192.

Stevenson RE, Procopio‐Allen AM, Schroer RJ and Collins JS (2003) Genetic syndromes among individuals with mental retardation. American Journal of Medical Genetics A 123: 29–32.

Toledano‐Alhadef H, Basel‐Vanagaite L, Magal N et al. (2001) Fragile‐X carrier screening and the prevalence of premutation and full‐mutation carriers in Israel. American Journal of Human Genetics 69: 351–360.

Turner G and Partington M (2000) Recurrence risks in undiagnosed mental retardation. Journal of Medical Genetics 37: E45.

Uyguner O, Kayserili H, Li Y et al. (2007) A new locus for autosomal recessive non‐syndromic mental retardation maps to 1p21.1‐p13.3. Clinical Genetics 71: 212–219.

de Vries BB, van den Ouweland AM, Mohkamsing S et al. (1997) Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey. Collaborative Fragile X Study Group. American Journal of Human Genetics 61: 660–667.

Zanni G, Saillour Y, Nagara M et al. (2005) Oligophrenin 1 mutations frequently cause X‐linked mental retardation with cerebellar hypoplasia. Neurology 65: 1364–1369.

Further Reading

Frints SG, Froyen G, Marynen P and Fryns JP (2002) X‐linked mental retardation: vanishing boundaries between non‐specific (MRX) and syndromic (MRXS) forms. Clinical Genetics 62: 423–432.

Madrigal I, Rodríguez‐Revenga L, Badenas C et al. (2007) MLPA as first screening method for the detection of microduplications and microdeletions in patients with X‐linked mental retardation. Genetics in Medicine 9: 117–122.

Poirier K, Lacombe D, Gilbert‐Dussardier B et al. (2006) Screening of ARX in mental retardation families: consequences for the strategy of molecular diagnosis. Neurogenetics 7: 39–46.

Raymond FL (2006) X linked mental retardation: a clinical guide. Journal of Medical Genetics 43: 193–200.

Raymond FL and Tarpey P (2006) The genetics of mental retardation. Human Molecular Genetics 15(Spec No 2): R110–R116.

Renieri A, Pescucci C, Longo I et al. (2005) Non‐syndromic X‐linked mental retardation: from a molecular to a clinical point of view. Journal of Cellular Physiology 204: 8–20.

Rosenberg C, Knijnenburg J, Bakker E et al. (2006) Array‐CGH detection of micro rearrangements in mentally retarded individuals: clinical significance of imbalances present both in affected children and normal parents. Journal of Medical Genetics 43: 180–186.

Shaffer LG, Bejjani BA, Torchia B et al. (2007) The identification of microdeletion syndromes and other chromosome abnormalities: cytogenetic methods of the past, new technologies for the future. American Journal of Medical Genetics C Seminars in Medical Genetics 145: 335–345.

de Vries BB, Pfundt R, Leisink M et al. (2005) Diagnostic genome profiling in mental retardation. American Journal of Human Genetics 77: 606–616.

Willems PJ (2007) Cognition genes on autosomes: the paradox. Clinical Genetics 72: 9–12.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Basel‐Vanagaite, Lina(Dec 2008) Molecular Genetics of Mental Retardation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021454]