1,371
Views
34
CrossRef citations to date
0
Altmetric
Review Article

Genetic diagnosis of autism spectrum disorders: The opportunity and challenge in the genomics era

, , , , &
Pages 249-262 | Received 16 Dec 2013, Accepted 30 Mar 2014, Published online: 30 May 2014

References

  • Kanner L. Autistic disturbances of affective contact. Nervous Child 1943;2:217–53
  • Folstein SR, M. Infantile autism: a genetic study of 21 twin pairs. J Child Psychol Psychiatry 1977;197:297–321
  • Bailey A, Le Couteur A, Gottesman I, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995;25:63–77
  • Hallmayer J, Cleveland S, Torres A, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 2011;68:1095–102
  • Hallmayer J, Glasson EJ, Bower C, et al. On the twin risk in autism. Am J Hum Genet 2002;71:941–6
  • Steffenburg S, Gillberg C, Hellgren L, et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 1989;30:405–16
  • Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999;23:185–8
  • Pieretti M, Zhang FP, Fu YH, et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 1991;66:817–22
  • State MW, Levitt P. The conundrums of understanding genetic risks for autism spectrum disorders. Nat Neurosci 2011;14:1499–506
  • Buxbaum JD, Daly MJ, Devlin B, et al. The Autism Sequencing Consortium: large-scale, high-throughput sequencing in autism spectrum disorders. Neuron 2012;76:1052–6
  • Geschwind DH. Autism: many genes, common pathways? Cell 2008;135:391–5
  • Schaaf CP, Goin-Kochel RP, Nowell KP, et al. Expanding the clinical spectrum of the 16p11.2 chromosomal rearrangements: three patients with syringomyelia. Eur J Hum Genet 2011;19:152–6
  • American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. Washington, DC: American Psychiatric Association, 2000:70–5
  • American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Washington, DC: American Psychiatric Association, 2013:50–9
  • Schaefer GB, Mendelsohn NJ, Professional P, et al. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med 2013;15:399–407
  • Jacquemont ML, Sanlaville D, Redon R, et al. Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet 2006;43:843–9
  • Beaudet AL. Autism: highly heritable but not inherited. Nat Med 2007;13:534–6
  • Prevalence of autism spectrum disorders – Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ 2012;61:1–19
  • Prevalence of autism spectrum disorders – Autism and Developmental Disabilities Monitoring Network, United States, 2006. MMWR Surveill Summ 2009;58:1–20
  • Gregory SG, Anthopolos R, Osgood CE, et al. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr 2013;167:959–66
  • Huguet G, Ey E, Bourgeron T. The genetic landscapes of autism spectrum disorders. Ann Rev Genom Hum Genet 2013;14:191–213
  • Devlin B, Scherer SW. Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev 2012;22:229–37
  • Stankiewicz P, Inoue K, Bi W, et al. Genomic disorders: genome architecture results in susceptibility to DNA rearrangements causing common human traits. Cold Spring Harb Symp Quant Biol 2003;68:445–54
  • Williams CA, Lossie A, Driscoll D. Angelman syndrome: mimicking conditions and phenotypes. Am J Med Genet 2001;101:59–64
  • Phelan MC. Deletion 22q13.3 syndrome. Orphanet J Rare Dis 2008;3:14–20
  • Laje G, Morse R, Richter W, et al. Autism spectrum features in Smith-Magenis syndrome. Am J Med Genet C Semin Med Genet 2010;154C:456–62
  • Potocki L, Bi W, Treadwell-Deering D, et al. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 2007;80:633–49
  • Cook EH Jr, Lindgren V, Leventhal BL, et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 1997;60:928–34
  • Roberts SE, Dennis NR, Browne CE, et al. Characterisation of interstitial duplications and triplications of chromosome 15q11-q13. Hum Genet 2002;110:227–34
  • Ingason A, Kirov G, Giegling I, et al. Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness. Am J Psychiatry 2011;168:408–17
  • Thomas NS, Durkie M, Potts G, et al. Parental and chromosomal origins of microdeletion and duplication syndromes involving 7q11.23, 15q11-q13 and 22q11. Eur J Hum Genet 2006;14:831–7
  • Boyar FZ, Whitney MM, Lossie AC, et al. A family with a grand-maternally derived interstitial duplication of proximal 15q. Clin Genet 2001;60:421–30
  • Bucan M, Abrahams BS, Wang K, et al. Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet 2009;5:e1000536
  • Wang NJ, Liu D, Parokonny AS, et al. High-resolution molecular characterization of 15q11-q13 rearrangements by array comparative genomic hybridization (array CGH) with detection of gene dosage. Am J Hum Genet 2004;75:267–81
  • Gurrieri F, Battaglia A, Torrisi L, et al. Pervasive developmental disorder and epilepsy due to maternally derived duplication of 15q11-q13. Neurology 1999;52:1694–7
  • Depienne C, Moreno-De-Luca D, Heron D, et al. Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders. Biol Psychiatry 2009;66:349–59
  • 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
  • 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
  • Sanders SJ, Ercan-Sencicek AG, Hus V, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 2011;70:863–85
  • Celestino-Soper PB, Shaw CA, Sanders SJ, et al. Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE. Hum Mol Genet 2011;20:4360–70
  • Toro R, Konyukh M, Delorme R, et al. Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends Genet 2010;26:363–72
  • Boone PM, Bacino CA, Shaw CA, et al. Detection of clinically relevant exonic copy-number changes by array CGH. Hum Mutat 2010;31:1326–42
  • Schaaf CP, Boone PM, Sampath S, et al. Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions. Eur J Hum Genet 2012;20:1240–7
  • Nagamani SC, Erez A, Ben-Zeev B, et al. Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders. Eur J Hum Genet 2013;21:343–6
  • Beunders G, Voorhoeve E, Golzio C, et al. Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. Am J Hum Genet 2013;92:210–20
  • 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
  • Bonaglia MC, Giorda R, Mani E, et al. Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome. J Med Genet 2006;43:822–8
  • Wilson HL, Wong AC, Shaw SR, et al. Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J Med Genet 2003;40:575–84
  • Boccuto L, Lauri M, Sarasua SM, et al. Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders. Eur J Hum Genet 2013;21:310–16
  • Moessner R, Marshall CR, Sutcliffe JS, et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 2007;81:1289–97
  • Talkowski ME, Mullegama SV, Rosenfeld JA, et al. Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. Am J Hum Genet 2011;89:551–63
  • Zweier C, de Jong EK, Zweier M, et al. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet 2009;85:655–66
  • Laumonnier F, Bonnet-Brilhault F, Gomot M, et al. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet 2004;74:552–7
  • Arking DE, Cutler DJ, Brune CW, et al. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 2008;82:160–4
  • Chahrour MH, Yu TW, Lim ET, et al. Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet 2012;8:e1002635
  • Iossifov I, Ronemus M, Levy D, et al. De novo gene disruptions in children on the autistic spectrum. Neuron 2012;74:285–99
  • Neale BM, Kou Y, Liu L, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012;485:242–5
  • O'Roak BJ, Vives L, Girirajan S, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012;485:246–50
  • Michaelson JJ, Shi Y, Gujral M, et al. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 2012;151:1431–42
  • Jiang YH, Yuen RK, Jin X, et al. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet 2013;93:249–63
  • Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012;485:237–41
  • Bi C, Wu J, Jiang T, et al. Mutations of ANK3 identified by exome sequencing are associated with autism susceptibility. Hum Mutat 2012;33:1635–8
  • Shi L, Zhang X, Golhar R, et al. Whole-genome sequencing in an autism multiplex family. Mol Autism 2013;4:8 . doi: 10.1186/2040-2392-4-8
  • Yu TW, Chahrour MH, Coulter ME, et al. Using whole-exome sequencing to identify inherited causes of autism. Neuron 2013;77:259–73
  • Lim ET, Raychaudhuri S, Sanders SJ, et al. Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron 2013;77:235–42
  • Szatmari P, Paterson AD, Zwaigenbaum L, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007;39:319–28
  • Devlin B, Melhem N, Roeder K. Do common variants play a role in risk for autism? Evidence and theoretical musings. Brain Res 2011;1380:78–84
  • Wang K, Zhang H, Ma D, et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 2009;459:528–33
  • Weiss LA. Autism genetics: emerging data from genome-wide copy-number and single nucleotide polymorphism scans. Expert Rev Mol Diagn 2009;9:795–803
  • Anney R, Klei L, Pinto D, et al. A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet 2010;19:4072–82
  • Weiss LA, Arking DE, Daly MJ, et al. A genome-wide linkage and association scan reveals novel loci for autism. Nature 2009;461:802–8
  • Anney R, Klei L, Pinto D, et al. Individual common variants exert weak effects on the risk for autism spectrum disorderspi. Hum Mol Genet 2012;21:4781–92
  • Zecavati N, Spence SJ. Neurometabolic disorders and dysfunction in autism spectrum disorders. Curr Neurol Neurosci Rep 2009;9:129–36
  • Johnson CP, Myers SM, American Academy of Pediatrics Council on Children with Disabilities. Identification and evaluation of children with autism spectrum disorders. Pediatrics 2007;120:1183–215
  • Zwaigenbaum L, Bryson S, Lord C, et al. Clinical assessment and management of toddlers with suspected autism spectrum disorder: insights from studies of high-risk infants. Pediatrics 2009;123:1383–91
  • Shen Y, Dies KA, Holm IA, et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 2010;125:e727–35
  • Herman GE, Henninger N, Ratliff-Schaub K, et al. Genetic testing in autism: how much is enough? Genet Med 2007;9:268–74
  • Ou Z, Kang SH, Shaw CA, et al. Bacterial artificial chromosome-emulation oligonucleotide arrays for targeted clinical array-comparative genomic hybridization analyses. Genet Med 2008;10:278–89
  • 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;22:79–87
  • Peiffer DA, Le JM, Steemers FJ, et al. High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping. Genome Res 2006;16:1136–48
  • Schwartz S. Clinical utility of single nucleotide polymorphism arrays. Clin Lab Med 2011;31:581–94
  • Papenhausen P, Schwartz S, Risheg H, et al. UPD detection using homozygosity profiling with a SNP genotyping microarray. Am J Med Genet A 2011;155A:757–68
  • Alkan C, Coe BP, Eichler EE. Genome structural variation discovery and genotyping. Nat Rev Genet 2011;12:363–76
  • Gamsiz ED, Viscidi EW, Frederick AM, et al. Intellectual disability is associated with increased runs of homozygosity in simplex autism. Am J Hum Genet 2013;93:103–9
  • Cohen D, Pichard N, Tordjman S, et al. Specific genetic disorders and autism: clinical contribution towards their identification. J Autism Dev Disord 2005;35:103–16
  • Myers SM, Johnson CP, American Academy of Pediatrics Council on Children with Disabilities. Management of children with autism spectrum disorders. Pediatrics 2007;120:1162–82
  • Rehm HL, Bale SJ, Bayrak-Toydemir P, et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med 2013;15:733–47
  • Jacob HJ. Next-generation sequencing for clinical diagnostics. N Engl J Med 2013;369:1557–8
  • Gahl WA, Markello TC, Toro C, et al. The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases. Genet Med 2012;14:51–9
  • Ng SB, Turner EH, Robertson PD, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 2009;461:272–6
  • Hoischen A, van Bon BW, Rodriguez-Santiago B, et al. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat Genet 2011;43:729–31
  • Gilissen C, Hoischen A, Brunner HG, et al. Unlocking Mendelian disease using exome sequencing. Genome Biol 2011;12:228–239
  • Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013;369:1502–11
  • Rodriguez-Flores JL, Fakhro K, Hackett NR, et al. Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar. Hum Mutat 2014;35:105–16
  • Patel AB, Hays SA, Bureau I, et al. A target cell-specific role for presynaptic Fmr1 in regulating glutamate release onto neocortical fast-spiking inhibitory neurons. J Neurosci 2013;33:2593–604
  • Stankiewicz P, Pursley AN, Cheung SW. Challenges in clinical interpretation of microduplications detected by array CGH analysis. Am J Med Genet A 2010;152A:1089–100
  • Hehir-Kwa JY, Pfundt R, Veltman JA, et al. Pathogenic or not?. Assessing the clinical relevance of copy number variants. Clin Genet 2013;84:415–21
  • Grabrucker AM, Knight MJ, Proepper C, et al. Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation. EMBO J 2011;30:569–81
  • Marshall CR, Noor A, Vincent JB, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 2008;82:477–88
  • 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
  • Golzio C, Willer J, Talkowski ME, et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 2012;485:363–7
  • Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013;339:819–23
  • Mali P, Yang L, Esvelt KM, et al. RNA-guided human genome engineering via Cas9. Science 2013;339:823–6
  • Leblond CS, Heinrich J, Delorme R, et al. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet 2012;8:e1002521
  • El-Fishawy P, State MW. The genetics of autism: key issues, recent findings, and clinical implications. Psychiatr Clin North Am 2010;33:83–105
  • Lupski JR, Belmont JW, Boerwinkle E, et al. Clan genomics and the complex architecture of human disease. Cell 2011;147:32–43
  • Zhu L, Wang X, Li XL, et al. Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders. Hum Mol Genet 2014;23:1563–78
  • Jiang YH, Sahoo T, Michaelis RC, et al. A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A. Am J Med Genet A 2004;131:1–10
  • Samaco RC, Hogart A, LaSalle JM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet 2005;14:483–92
  • Green RC, MD, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013:15:565–74
  • Kumar RA, KaraMohamed S, Sudi J, et al. Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 2008;17:628–38
  • 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
  • Bochukova EG, Huang N, Keogh J, et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 2010;463:666–70
  • Shen Y, Chen X, Wang L, et al. Intra-family phenotypic heterogeneity of 16p11.2 deletion carriers in a three-generation Chinese family. Am J Med Genet B Neuropsychiatr Genet 2011;156:225–32
  • 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
  • Puvabanditsin S, Nagar MS, Joshi M, et al. Microdeletion of 16p11.2 associated with endocardial fibroelastosis. Am J Med Genet A 2010;152A:2383–6
  • Miller DT NR, Sobeih MM, Shen Y, Wu BL, Hanson E. 16p11.2 microdeletion. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews [Internet]. Seattle (WA): University of Washington; 1993–2014. 2009 Sep 22 [updated 2011 Oct 27]
  • McCarthy SE, Makarov V, Kirov G, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 2009;41:1223–7
  • Simons Vip Consortium. Simons Variation in Individuals Project (Simons VIP): a genetics-first approach to studying autism spectrum and related neurodevelopmental disorders. Neuron 2012;73:1063–7
  • Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012;367:2175–84
  • Law LW, Lau TK, Fung TY, et al. De novo 16p13.11 microdeletion identified by high-resolution array CGH in a fetus with increased nuchal translucency. BJOG 2009;116:339–43
  • Poot M, Verrijn Stuart AA, van Daalen E, et al. Variable behavioural phenotypes of patients with monosomies of 15q26 and a review of 16 cases. Eur J Med Genet 2013;56:346–50
  • Choy KW, Setlur SR, Lee C, et al. The impact of human copy number variation on a new era of genetic testing. BJOG 2010;117:391–8

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.