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Open Access 01-12-2010 | Review

"Idiopathic" mental retardation and new chromosomal abnormalities

Authors: Cinzia Galasso, Adriana Lo-Castro, Nadia El-Malhany, Paolo Curatolo

Published in: Italian Journal of Pediatrics | Issue 1/2010

Abstract

Mental retardation is a heterogeneous condition, affecting 1-3% of general population. In the last few years, several emerging clinical entities have been described, due to the advent of newest genetic techniques, such as array Comparative Genomic Hybridization. The detection of cryptic microdeletion/microduplication abnormalities has allowed genotype-phenotype correlations, delineating recognizable syndromic conditions that are herein reviewed. With the aim to provide to Paediatricians a combined clinical and genetic approach to the child with cognitive impairment, a practical diagnostic algorithm is also illustrated. The use of microarray platforms has further reduced the percentage of "idiopathic" forms of mental retardation, previously accounted for about half of total cases. We discussed the putative pathways at the basis of remaining "pure idiopathic" forms of mental retardation, highlighting possible environmental and epigenetic mechanisms as causes of altered cognition.

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Vissers LE, de Vries BB, Veltman JA: Genomic microarrays in mental retardation: from CNV to gene, from research to diagnosis. J Med Genet. 2009,

Bernardini L, Alesi V, Loddo S, Novelli A, Bottillo I, Battaglia A, Digilio MC, Zampino G, Ertel A, Fortina P, Surrey S, Dallapiccola B: High-resolution SNP arrays in mental retardation diagnostics: how much do we gain?. Eur J Hum Genet. 2010, 18: 178-185. 10.1038/ejhg.2009.154.PubMedCentralPubMedCrossRef

Shevell MI, Bejjani BA, Srour M, Rorem EA, Hall N, Shaffer LG: Array comparative genomic hybridization in global developmental delay. Am J Med Genet. 2008, 147B: 1101-1108. 10.1002/ajmg.b.30730.PubMedCrossRef

Shaffer LG, Bejjani BA, Torchia B, Kirkpatrick S, Coppinger J, Ballif BC: The identification of microdeletion syndromes and other chromosome abnormalities: cytogenetic methods of the past, new technologies for the future. Am J Med Genet. 2007, 145C: 335-345. 10.1002/ajmg.c.30152.PubMedCrossRef

Li MM, Andersson HC: Clinical Application of Microarray-Based Molecular Cytogenetics: An Emerging New Era of Genomic Medicine. J Pediatr. 2009, 155: 311-317. 10.1016/j.jpeds.2009.04.001.PubMedCrossRef

Liang JS, Shimojima K, Yamamoto T: Application of Array-based Comparative Genome Hybridization in Children with Developmental Delay or Mental Retardation. Pediatr Neonatol. 2008, 49: 213-217. 10.1016/S1875-9572(09)60013-9.PubMedCrossRef

Hall DMB: Birth asphyxia and cerebral palsy. BMJ. 1989, 299: 279-282. 10.1136/bmj.299.6694.279.PubMedCentralPubMedCrossRef

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: 60-66. 10.1002/(SICI)1096-8628(19990101)82:1<60::AID-AJMG12>3.0.CO;2-4.PubMedCrossRef

Battaglia A, Carey JC: Diagnostic evaluation of developmental delay/mental retardation: An overview. Am J Med Genet. 2003, 117C: 3-14. 10.1002/ajmg.c.10015.PubMedCrossRef

10.

Cassidy SB, Morris CA: Behavioral phenotypes in genetic syndromes: genetic clues to human behavior. Adv Pediatr. 2002, 49: 59-86.PubMed

11.

Stankiewicz P, Beaudet AL: Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev. 2007, 17: 182-192. 10.1016/j.gde.2007.04.009.PubMedCrossRef

12.

Gijsbers AC, Lew JY, Bosch CA, Schuurs-Hoeijmakers JH, van Haeringen A, den Hollander NS, Kant SG, Bijlsma EK, Breuning MH, Bakker E, Ruivenkamp CA: A new diagnostic workflow for patients with mental retardation and/or multiple congenital abnormalities: test arrays first. Eur J Hum Genet. 2009, 17: 1394-1402. 10.1038/ejhg.2009.74.PubMedCentralPubMedCrossRef

13.

Paciorkowski AR, Fang M: Chromosomal microarray interpretation: what is a child neurologist to do?. Pediatr Neurol. 2009, 41: 391-398. 10.1016/j.pediatrneurol.2009.05.003.PubMedCrossRef

14.

Hochstenbach R, van Binsbergen E, Engelen J, Nieuwint A, Polstra A, Poddighe P, Ruivenkamp C, Sikkema-Raddatz B, Smeets D, Poot M: 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: 161-169. 10.1016/j.ejmg.2009.03.015.PubMedCrossRef

15.

Webber C, Hehir-Kwa JY, DC Nguyen, de Vries BBA, Veltman JA, Ponting CP: Forging Links between Human Mental Retardation-Associated CNVs and Mouse Gene Knockout Models. PLoS Genet. 2009, 5: e1000531-10.1371/journal.pgen.1000531.PubMedCentralPubMedCrossRef

16.

Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y, Aerts J, Andrews TD, Barnes C, Campbell P, Fitzgerald T, Hu M, Ihm CH, Kristiansson K, Macarthur DG, Macdonald JR, Onyiah I, Pang AW, Robson S, Stirrups K, Valsesia A, Walter K, Wei J, The Wellcome Trust Case Control Consortium, Tyler-Smith C, Carter NP, Lee C, Scherer SW, Hurles ME: Origins and functional impact of copy number variation in the human genome. Nature. 2009,

17.

Koolen DA, Pfundt R, de Leeuw N, Hehir-Kwa JY, Nillesen WM, Neefs I, Scheltinga I, Sistermans E, Smeets D, Brunner HG, van Kessel AG, Veltman JA, de Vries BBA: Genomic Microarrays in Mental Retardation: A Practical Workflow for Diagnostic Applications. Hum Mutat. 2009, 30: 283-292. 10.1002/humu.20883.PubMedCrossRef

18.

Bruno DL, Ganesamoorthy D, Schoumans J, Bankier A, Coman D, Delatycki M, Gardner RJM, Hunter M, James PA, Kannu P, McGillivray G, Pachter N, Peters H, Rieubland C, Savarirayan R, Scheffer IE, Sheffield L, Tan T, White SM, Yeung A, Bowman Z, Ngo C, Choy KW, Cacheux V, Wong L, Amor DJ, Slater HR: Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice. J Med Genet. 2009, 46: 123-131. 10.1136/jmg.2008.062604.PubMedCrossRef

19.

Gajecka M, Mackay KL, Shaffer LG: Monosomy 1p36 deletion syndrome. Am J Med Gen. 2007, 145C: 346-356. 10.1002/ajmg.c.30154.CrossRef

20.

Battaglia A: Del 1p36 syndrome: a newly emerging clinical entity. Brain Dev. 2005, 27: 358-361. 10.1016/j.braindev.2004.03.011.PubMedCrossRef

21.

van Bon BW, Koolen DA, Brueton L, McMullan D, Lichtenbelt KD, Adès LC, Peters G, Gibson K, Novara F, Pramparo T, Bernardina BD, Zoccante L, Balottin U, Piazza F, Pecile V, Gasparini P, Guerci V, Kets M, Pfundt R, de Brouwer AP, Veltman JA, de Leeuw N, Wilson M, Antony J, Reitano S, Luciano D, Fichera M, Romano C, Brunner HG, Zuffardi O, de Vries BB: The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. Eur J Hum Genet. 2010, 18: 163-170. 10.1038/ejhg.2009.152.PubMedCentralPubMedCrossRef

22.

Jaillard S, Dubourg C, Gérard-Blanluet M, Delahaye A, Pasquier L, Dupont C, Henry C, Tabet AC, Lucas J, Aboura A, David V, Benzacken B, Odent S, Pipiras E: 2q23.1 microdeletion identified by array comparative genomic hybridisation: an emerging phenotype with Angelman-like features?. J Med Genet. 2009, 46: 847-855. 10.1136/jmg.2008.058156.PubMedCentralPubMedCrossRef

23.

Williams SR, Mullegama SV, Rosenfeld JA, Dagli AI, Hatchwell E, Allen WP, Williams CA, Elsea SH: Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Eur J Hum Genet. 2009,

24.

Falk RE, Casas KA: Chromosome 2q37 deletion: clinical and molecular aspects. Am J Med Genet. 2009, 145C: 357-371. 10.1002/ajmg.c.30153.CrossRef

25.

Galasso C, Lo-Castro A, Lalli C, Nardone AM, Gullotta F, Curatolo P: Deletion 2q 37: An identifiable clinical syndrome with mental retardation and autism. J Child Neurol. 2008, 23: 802-806. 10.1177/0883073808314150.PubMedCrossRef

26.

Depienne C, Heron D, Betancur C, Benyahia B, Trouillard O, Bouteiller D, Verloes A, LeGuern E, Leboyer M, Brice A: Autism, language delay and mental retardation in a patient with 7q11 duplication. J Med Genet. 2007, 44: 452-458. 10.1136/jmg.2006.047092.PubMedCentralPubMedCrossRef

27.

Gu W, Lupski JR: CNV and nervous system diseases-what's new?. Cytogenet Genome Res. 2008, 123: 54-64. 10.1159/000184692.PubMedCrossRef

28.

Van der Aa N, Rooms L, Vandeweyer G, Van den Ende J, Reyniers E, Fichera M, Romano C, Delle Chiaie B, Mortier G, Menten B, Destrée A, Maystadt I, Männik K, Kurg A, Reimand T, McMullan D, Oley C, Brueton L, Bongers EM, van Bon BW, Pfund R, Jacquemont S, Ferrarini A, Martinet D, Schrander-Stumpel C, Stegmann AP, Frints SG, de Vries BB, Ceulemans B, Kooy RF: Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. Eur J Med Genet. 2009, 52: 94-100. 10.1016/j.ejmg.2009.02.006.PubMedCrossRef

29.

Slavotinek AM: Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet. 2008, 124: 1-17. 10.1007/s00439-008-0513-9.PubMedCrossRef

30.

Dibbens LM, Mullen S, Helbig I, Mefford HC, Bayly MA, Bellows S, Leu C, Trucks H, Obermeier T, Wittig M, Franke A, Caglayan H, Yapici Z, EPICURE Consortium, Sander T, Eichler EE, Scheffer IE, Mulley JC, Berkovic SF: Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum Mol Genet. 2009, 18: 3626-3631. 10.1093/hmg/ddp311.PubMedCentralPubMedCrossRef

31.

van Bon BW, Mefford HC, Menten B, Koolen DA, Sharp AJ, Nillesen WM, Innis JW, de Ravel TJ, Mercer CL, Fichera M, Stewart H, Connell LE, Ounap K, Lachlan K, Castle B, van der Aa N, van Ravenswaaij C, Nobrega MA, Serra-Juhé C, Simonic I, de Leeuw N, Pfundt R, Bongers EM, Baker C, Finnemore P, Huang S, Maloney VK, Crolla JA, van Kalmthout M, Elia M, Vandeweyer G, Fryns JP, Janssens S, Foulds N, Reitano S, Smith K, Parkel S, Loeys B, Woods CG, Oostra A, Speleman F, Pereira AC, Kurg A, Willatt L, Knight SJ, Vermeesch JR, Romano C, Barber JC, Mortier G, Pérez-Jurado LA, Kooy F, Brunner HG, Eichler EE, Kleefstra T, de Vries BB: A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. J Med Genet. 2009, 46: 511-523. 10.1136/jmg.2008.063412.PubMedCentralPubMedCrossRef

32.

Kumar RA, KaraMohamed S, Sudi J, Conrad DF, Brune C, Badner JA, Gilliam TC, Nowak NJ, Cook EH, Dobyns WB, Christian SL: Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet. 2008, 17: 628-638. 10.1093/hmg/ddm376.PubMedCrossRef

33.

Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL, Daly MJ, Autism Consortium: Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008, 358: 667-675. 10.1056/NEJMoa075974.PubMedCrossRef

34.

Battaglia A, Novelli A, Bernardini L, Igliozzi R, Parrini B: Further characterization of the new microdeletion syndrome of 16p11.2-p12.2. Am J Med Genet. 2009, 149A: 1200-1204. 10.1002/ajmg.a.32847.PubMedCrossRef

35.

Hempel M, Rivera Brugués N, Wagenstaller J, Lederer G, Weitensteiner A, Seidel H, Meitinger T, Strom TM: Microdeletion syndrome 16p11.2-p12.2: clinical and molecular characterization. Am J Med Genet A. 2009, 149A: 2106-2112. 10.1002/ajmg.a.33042.PubMedCrossRef

36.

Bijlsma EK, Gijsbers AC, Schuurs-Hoeijmakers JH, van Haeringen A, Fransen van de Putte DE, Anderlid BM, Lundin J, Lapunzina P, Pérez Jurado LA, Delle Chiaie B, Loeys B, Menten B, Oostra A, Verhelst H, Amor DJ, Bruno DL, van Essen AJ, Hordijk R, Sikkema-Raddatz B, Verbruggen KT, Jongmans MC, Pfundt R, Reeser HM, Breuning MH, Ruivenkamp CA: Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals. Eur J Med Genet. 2009, 52: 77-87. 10.1016/j.ejmg.2009.03.006.PubMedCrossRef

37.

Koolen DA, Sharp AJ, Hurst JA, Firth HV, Knight SJ, Goldenberg A, Saugier-Veber P, Pfundt R, Vissers LE, Destrée A, Grisart B, Rooms L, Vand der Aa N, Field M, Hackett A, Bell K, Nowaczyk MJ, Mancini GM, Poddighe PJ, Schwartz CE, Rossi E, De Gregori M, Antonacci-Fulton LL, McLellan MD, Garrett JM, Wiechert MA, Miner TL, Crosby S, Ciccone R, Willatt L, Rauch A, Zenker M, Aradhya S, Manning MA, Strom TM, Wagenstaller J, Krepischi-Santos AC, Vianna-Morgante AM, Rosenberg C, Price SM, Stewart H, Shaw-Smith C, Brunner HG, Wilkie AO, Veltman JA, Zuffardi O, Eichler EE, de Vries BB: Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J Med Genet. 2008, 45: 710-720. 10.1136/jmg.2008.058701.PubMedCentralPubMedCrossRef

38.

Tan TY, Aftimos S, Worgan L, Susman R, Wilson M, Ghedia S, Kirk EP, Love D, Ronan A, Darmanian A, Slavotinek A, Hogue J, Moeschler JB, Ozmore J, Widmer R, Bruno D, Savarirayan R, Peters G: Phenotypic expansion and further characterisation of the 17q21.31 microdeletion syndrome. J Med Genet. 2009, 46: 480-489. 10.1136/jmg.2008.065391.PubMedCrossRef

39.

Portnoï MF: Microduplication 22q11.2: A new chromosomal syndrome. Eur J Med Gen. 2009, 52: 88-93. 10.1016/j.ejmg.2009.02.008.CrossRef

40.

Lo-Castro A, Galasso C, Cerminara C, El-Malhany N, Benedetti S, Nardone AM, Curatolo P: Association of syndromic mental retardation and autism with 22q11.2 duplication. Neuropediatrics. 2009, 40: 137-140. 10.1055/s-0029-1237724.PubMedCrossRef

41.

Ropers HH: Genetics of intellectual disability. Curr Opin Genet Dev. 2008, 18: 241-250. 10.1016/j.gde.2008.07.008.PubMedCrossRef

42.

Kalia M: Brain development: anatomy, connectivity, adaptive plasticity, and toxicity. Metabolism. 2008, 57 (Suppl 2): S2-5. 10.1016/j.metabol.2008.07.009.PubMedCrossRef

43.

Urdinguio RG, Sanchez-Mut JV, Esteller M: Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol. 2009, 8: 1056-1072. 10.1016/S1474-4422(09)70262-5.PubMedCrossRef

44.

Gräff J, Mansuy IM: Epigenetic dysregulation in cognitive disorders. Eur J Neurosci. 2009, 30: 1-8. 10.1111/j.1460-9568.2009.06787.x.PubMedCrossRef

Title: "Idiopathic" mental retardation and new chromosomal abnormalities
Authors: Cinzia Galasso
Adriana Lo-Castro
Nadia El-Malhany
Paolo Curatolo
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: Italian Journal of Pediatrics / Issue 1/2010
Electronic ISSN: 1824-7288
DOI: https://doi.org/10.1186/1824-7288-36-17

Keynote webinar | Spotlight on medication adherence

Springer Medicine

"Idiopathic" mental retardation and new chromosomal abnormalities

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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