Genomics, intellectual disability, and autism

New England Journal of Medicine

Volumn 366, Issue 8, 2012, Pages 733-743

  Mefford, Heather C ^a   Batshaw, Mark L ^b   Hoffman, Eric P ^b  

^a UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^b GEORGE WASHINGTON UNIVERSITY SCHOOL OF MEDICINE AND HEALTH SCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DNA FRAGMENT;

AUTISM; CHROMOSOME; CHROMOSOME 10Q; CHROMOSOME 15Q; CHROMOSOME 16P; CHROMOSOME 17Q; CHROMOSOME 1Q; CHROMOSOME 21; CHROMOSOME 3Q; CHROMOSOME BANDING PATTERN; CHROMOSOME DUPLICATION; COMPARATIVE GENOMIC HYBRIDIZATION; COPY NUMBER VARIATION; DNA CONTENT; DNA SEQUENCE; DOWN SYNDROME; EMR1 GENE; EPILEPSY; EXOME; FLUORESCENCE IN SITU HYBRIDIZATION; FOXP1 GENE; FREEMAN SHELDON SYNDROME; GENE; GENE DELETION; GENE TRANSLOCATION; GENETIC ASSOCIATION; GENETIC LINKAGE; GENOMICS; GENOTYPE; GRIN2B GENE; HETEROZYGOSITY; HOMOZYGOSITY; HUMAN; INTELLECTUAL IMPAIRMENT; KANUKI SYNDROME; KARYOTYPE; LAMC3 GENE; MECP2 GENE; MICROARRAY ANALYSIS; MLL2 GENE; PATHOGENESIS; PHENOTYPE; PRACTICE GUIDELINE; PRIORITY JOURNAL; PTEN GENE; REVIEW; SCHINZEL GIEDION SYNDROME; SCHIZOPHRENIA; SCN1A GENE; SEQUENCE ANALYSIS; SETBP1 GENE; SHANK3 GENE; SINGLE NUCLEOTIDE POLYMORPHISM;

EID: 84857434829     PISSN: 00284793     EISSN: 15334406     Source Type: Journal    
DOI: 10.1056/NEJMra1114194     Document Type: Review

References (110)

1. Diagnostic criteria from DSM-IV-TR. Washington, DC: American Psychiatric Association, 2000.
2. Leonard H, Wen X. The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev 2002;8:117-34. (Pubitemid 36378154)
3. Lejeune J, Gautier M, Turpin R. Etudes des chromosomes somatique de neuf enfants mongoliens. CR Hebd Seances Acad Sci 1959;248:1721-2.
4. Chakrabarti S, Fombonne E. Pervasive developmental disorders in preschool children. JAMA 2001;285:3093-9. (Pubitemid 32578206)
5. Idem. Pervasive developmental disorders in preschool children: confirmation of high prevalence. Am J Psychiatry 2005;162:1133-41.
6. Iafrate AJ, Feuk L, Rivera MN, et al. Detection of large-scale variation in the human genome. Nat Genet 2004;36:949-51. (Pubitemid 39167488)
7. Itsara A, Cooper GM, Baker C, et al. Population analysis of large copy number variants and hotspots of human genetic disease. Am J Hum Genet 2009;84:148-61.
8. Locke DP, Sharp AJ, McCarroll SA, et al. Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome. Am J Hum Genet 2006;79:275-90. (Pubitemid 44141826)
9. Redon R, Ishikawa S, Fitch KR, et al. Global variation in copy number in the human genome. Nature 2006;444:444-54. (Pubitemid 44809057)
10. Sebat J, Lakshmi B, Troge J, et al. Large-scale copy number polymorphism in the human genome. Science 2004;305:525-8. (Pubitemid 38971344)
11. Ropers HH. Genetics of intellectual disability. Curr Opin Genet Dev 2008;18:241-50.
12. Butler MG, Meaney FJ, Palmer CG. Clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome. Am J Med Genet 1986;23:793-809. (Pubitemid 16035050)
13. Pérez Jurado LA, Peoples R, Kaplan P, Hamel BC, Francke U. Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth. Am J Hum Genet 1996;59:781-92. (Pubitemid 26328073)
14. Smith AC, McGavran L, Robinson J, et al. Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am J Med Genet 1986;24:393-414. (Pubitemid 16017634)
15. Hogart A, Wu D, LaSalle JM, Schanen NC. The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13. Neurobiol Dis 2010;38:181-91.
16. Ballif BC, Sulpizio SG, Lloyd RM, et al. The clinical utility of enhanced subtelomeric coverage in array CGH. Am J Med Genet A 2007;143A:1850-7. (Pubitemid 47206059)
17. Knight SJ, Regan R, Nicod A, et al. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 1999;354:1676-81. (Pubitemid 29533057)
18. Ravnan JB, Tepperberg JH, Papenhausen P, et al. Subtelomere FISH analysis of 11 688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities. J Med Genet 2006;43:478-89. (Pubitemid 43927321)
19. de Vries BB, Pfundt R, Leisink M, et al. Diagnostic genome profiling in mental retardation. Am J Hum Genet 2005;77:606-16. (Pubitemid 41361607)
20. Koolen DA, Vissers LE, Pfundt R, et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet 2006;38:999-1001. (Pubitemid 44325923)
21. Sagoo GS, Butterworth AS, Sanderson S, Shaw-Smith C, Higgins JP, Burton H. 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;11:139-46.
22. Shaffer LG, Kashork CD, Saleki R, et al. Targeted genomic microarray analysis for identification of chromosome abnormalities in 1500 consecutive clinical cases. J Pediatr 2006;149:98-102. [Erratum, J Pediatr 2006;149:585.]
23. Sharp AJ, Hansen S, Selzer RR, et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 2006;38:1038-42. (Pubitemid 44325929)
24. Shaw-Smith C, Pittman AM, Willatt L, et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet 2006;38:1032-7. (Pubitemid 44325928)
25. Christian SL, Brune CW, Sudi J, et al. Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol Psychiatry 2008;63:1111-7.
26. Marshall CR, Noor A, Vincent JB, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 2008;82:477-88.
27. Sebat J, Lakshmi B, Malhotra D, et al. Strong association of de novo copy number mutations with autism. Science 2007;316:445-9. (Pubitemid 46651493)
28. Szatmari P, Paterson AD, Zwaigenbaum L, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007;39:319-28. (Pubitemid 46328498)
29. Weiss LA, Shen Y, Korn JM, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008;358:667-75. (Pubitemid 351240746)
30. Pinto D, Pagnamenta AT, Klei L, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 2010;466:368-72.
31. Mefford HC, Eichler EE. Duplication hotspots, rare genomic disorders, and common disease. Curr Opin Genet Dev 2009;19:196-204.
32. Brunetti-Pierri N, Berg JS, Scaglia F, et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet 2008;40:1466-71.
33. Mefford HC, Sharp AJ, Baker C, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 2008;359:1685-99.
34. International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008;455:237-41.
35. Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008;455:232-6.
36. Greenway SC, Pereira AC, Lin JC, et al. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet 2009;41:931-5.
37. Haldeman-Englert C, Jewett T. 1q21.1 Microdeletion. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews. Seattle: University of Washington, 1993.
38. Ballif BC, Theisen A, Coppinger J, et al. Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Mol Cytogenet 2008;1:8.
39. Lisi EC, Hamosh A, Doheny KF, et al. 3q29 Interstitial microduplication: a new syndrome in a three-generation family. Am J Med Genet A 2008;146A:601-9.
40. Willatt L, Cox J, Barber J, et al. 3q29 Microdeletion syndrome: clinical and molecular characterization of a new syndrome. Am J Hum Genet 2005;77:154-60. (Pubitemid 40848047)
41. Balciuniene J, Feng N, Iyadurai K, et al. Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities. Am J Hum Genet 2007;80:938-47. (Pubitemid 46668462)
42. van Bon BW, Balciuniene J, Fruhman G, et al. The phenotype of recurrent 10q22q23 deletions and duplications. Eur J Hum Genet 2011;19:400-8.
43. de Kovel CG, Trucks H, Helbig I, et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 2010;133:23-32.
44. Mefford HC, Cooper GM, Zerr T, et al. A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Res 2009;19:1579-85.
45. Burnside RD, Pasion R, Mikhail FM, et al. Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay. Hum Genet 2011;130:517-28.
46. Doornbos M, Sikkema-Raddatz B, Ruijvenkamp CA, et al. Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet 2009;52:108-15.
47. Murthy SK, Nygren AO, El Shakankiry HM, et al. Detection of a novel familial deletion of four genes between BP1 and BP2 of the Prader-Willi/Angelman syndrome critical region by oligo-array CGH in a child with neurological disorder and speech impairment. Cytogenet Genome Res 2007;116:135-40. (Pubitemid 46197145)
48. von der Lippe C, Rustad C, Heimdal K, Rodningen OK. 15q11.2 Microdeletion - seven new patients with delayed development and/or behavioural problems. Eur J Med Genet 2011;54:357-60.
49. Helbig I, Mefford HC, Sharp AJ, et al. 15q13.3 Microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 2009;41:160-2.
50. Sharp AJ, Mefford HC, Li K, et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 2008;40:322-8. (Pubitemid 351311774)
51. van Bon BW, Mefford HC, Menten B, et al. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 2009;46:511-23.
52. Ben-Shachar S, Lanpher B, German JR, et al. Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J Med Genet 2009;46:382-8.
53. Pagnamenta AT, Wing K, Akha ES, et al. A 15q13.3 microdeletion segregating with autism. Eur J Hum Genet 2009;17:687-92.
54. Miller DT, Shen Y, Weiss LA, et al. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 2009;46:242-8.
55. Andrieux J, Dubourg C, Rio M, et al. Genotype-phenotype correlation in four 15q24 deleted patients identified by array-CGH. Am J Med Genet A 2009;149A:2813-9.
56. Sharp AJ, Selzer RR, Veltman JA, et al. Characterization of a recurrent 15q24 microdeletion syndrome. Hum Mol Genet 2007;16:567-72. (Pubitemid 46522619)
57. Mefford HC, Rosenfeld JA, Shur N, et al. Further clinical and molecular delineation of the 15q24 microdeletion syndrome. J Med Genet 2012;49:110-8.
58. El-Hattab AW, Zhang F, Maxim R, et al. Deletion and duplication of 15q24: molecular mechanisms and potential modification by additional copy number variants. Genet Med 2010;12:573-86.
59. 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 A 2009;149A:1200-4.
60. Bijlsma EK, Gijsbers AC, Schuurs-Hoeijmakers JH, et al. 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.
61. Hempel M, Rivera Brugués N, Wagenstaller J, et al. Microdeletion syndrome 16p11.2-p12.2: clinical and molecular characterization. Am J Med Genet A 2009;149A:2106-12.
62. Shinawi M, Liu P, Kang SH, et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet 2010;47:332-41.
63. Jacquemont S, Reymond A, Zufferey F, et al. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature 2011;478:97-102.
64. Walters RG, Jacquemont S, Valsesia A, et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 2010;463:671-5.
65. McCarthy SE, Makarov V, Kirov G, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 2009;41:1223-7.
66. Bachmann-Gagescu R, Mefford HC, Cowan C, et al. Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med 2010;12:641-7.
67. Bochukova EG, Huang N, Keogh J, et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 2010;463:666-70.
68. Girirajan S, Rosenfeld JA, Cooper GM, et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet 2010;42:203-9.
69. Heinzen EL, Radtke RA, Urban TJ, et al. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet 2010;86:707-18.
70. Williams NM, Zaharieva I, Martin A, et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet 2010;376:1401-8.
71. Ullmann R, Turner G, Kirchhoff M, et al. Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum Mutat 2007;28:674-82. (Pubitemid 47047294)
72. Kirov G, Grozeva D, Norton N, et al. Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet 2009;18:1497-503.
73. Moreno-De-Luca D, Mulle JG, Kaminsky EB, et al. Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. Am J Hum Genet 2010;87:618-30. [Erratum, Am J Hum Genet 2011;88:121.]
74. Loirat C, Bellanné-Chantelot C, Husson I, Deschênes G, Guigonis V, Chabane N. Autism in three patients with cystic or hyperechogenic kidneys and chromosome 17q12 deletion. Nephrol Dial Transplant 2010;25:3430-3.
75. Koolen DA, Sharp AJ, Hurst JA, et al. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J Med Genet 2008;45:710-20. [Erratum, J Med Genet 2009;46:576.]
76. El-Hattab AW, Smolarek TA, Walker ME, et al. Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping. Hum Genet 2009;126:589-602.
77. Klopocki E, Graul-Neumann LM, Grieben U, et al. A further case of the recurrent 15q24 microdeletion syndrome, detected by array CGH. Eur J Pediatr 2008;167:903-8. (Pubitemid 351904600)
78. Christiansen J, Dyck JD, Elyas BG, et al. Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Circ Res 2004;94:1429-35. (Pubitemid 38780315)
79. Kumar RA, KaraMohamed S, Sudi J, et al. Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 2008;17:628-38.
80. Rosenfeld JA, Coppinger J, Bejjani BA, et al. Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications. J Neurodev Disord 2009;2:26-38.
81. 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;86:749-64.
82. Cooper GM, Coe BP, Girirajan S, et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011;43:838-46.
83. Manning M, Hudgins L. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med 2010;12:742-5.
84. Mefford HC, Muhle H, Ostertag P, et al. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet 2010;6(5):e1000962.
85. Lionel AC, Crosbie J, Barbosa N, et al. Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Sci Transl Med 2011;3:95ra75.
86. Ramalingam A, Zhou XG, Fiedler SD, et al. 16p13.11 Duplication is a risk factor for a wide spectrum of neuropsychiatric disorders. J Hum Genet 2011;56:541-4.
87. Dibbens LM, Mullen S, Helbig I, et al. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum Mol Genet 2009;18:3626-31.
88. Hannes FD, Sharp AJ, Mefford HC, et al. Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet 2009;46:223-32.
89. Grozeva D, Conrad DF, Barnes CP, et al. Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia. Schizophr Res 2011 November 28 (Epub ahead of print).
90. Tarpey PS, Smith R, Pleasance E, et al. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet 2009;41:535-43.
91. Ropers HH. Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet 2010;11:161-87.
92. Butler MG, Dasouki MJ, Zhou XP, et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 2005;42:318-21. (Pubitemid 40523954)
93. Durand CM, Betancur C, Boeckers TM, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 2007;39:25-7. (Pubitemid 46026497)
94. Sanger F, Air GM, Barrell BG, et al. Nucleotide sequence of bacteriophage phi X174 DNA. Nature 1977;265:687-95. (Pubitemid 8039446)
95. Feero WG, Guttmacher AE, Collins FS. Genomic medicine - an updated primer. N Engl J Med 2010;362:2001-11.
96. Shendure J, Ji H. Next-generation DNA sequencing. Nat Biotechnol 2008;26:1135-45.
97. Ng SB, Bigham AW, Buckingham KJ, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 2010;42:790-3.
98. Hoischen A, van Bon BW, Gilissen C, et al. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat Genet 2010;42:483-5.
99. Vissers LE, de Ligt J, Gilissen C, et al. A de novo paradigm for mental retardation. Nat Genet 2010;42:1109-12.
100. Najmabadi H, Hu H, Garshasbi M, et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 2011;478:57-63.
101. Calişkan M, Chong JX, Uricchio L, et al. Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13. Hum Mol Genet 2011;20:1285-9.
102. O'Roak BJ, Deriziotis P, Lee C, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 2011;43:585-9.
103. Ng SB, Turner EH, Robertson PD, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 2009;461:272-6.
104. Lynch M. Rate, molecular spectrum, and consequences of human mutation. Proc Natl Acad Sci U S A 2010;107:961-8.
105. Hamdan FF, Daoud H, Rochefort D, et al. De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. Am J Hum Genet 2010;87:671-8.
106. Endele S, Rosenberger G, Geider K, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 2010;42:1021-6.
107. Claes L, Ceulemans B, Audenaert D, et al. De novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy. Hum Mutat 2003;21:615-21. (Pubitemid 36667351)
108. Barak T, Kwan KY, Louvi A, et al. Recessive LAMC3 mutations cause malformations of occipital cortical development. Nat Genet 2011;43:590-4.
109. Choi M, Scholl UI, Ji W, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A 2009;106:19096-101.
110. Ng SB, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 2010;42:30-5.