Autism genetics: Opportunities and challenges for clinical translation

Nature Reviews Genetics

Volumn 18, Issue 6, 2017, Pages 362-376

  Vorstman, Jacob A S ^a   Parr, Jeremy R ^b   Moreno De Luca, Daniel ^c   Anney, Richard J L ^d   Nurnberger, John I ^e   Hallmayer, Joachim F ^f  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

^c BROWN UNIVERSITY   (United States)

^d CARDIFF UNIVERSITY   (United Kingdom)

^e INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^f STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AUTISM; CLINICAL PRACTICE; FAMILY HISTORY; GENE TECHNOLOGY; GENETIC COUNSELING; GENETIC RISK; GENETIC SCREENING; GENETIC VARIABILITY; GENOTYPE PHENOTYPE CORRELATION; HEALTH CARE PERSONNEL; HUMAN; MEDICAL EDUCATION; MOLECULAR GENETICS; MOLECULAR PATHOLOGY; PRIORITY JOURNAL; REVIEW; AUTISTIC DISORDER; GENETIC PREDISPOSITION; GENETICS; GENOTYPING TECHNIQUE; PATHOPHYSIOLOGY;

AUTISTIC DISORDER; GENETIC PREDISPOSITION TO DISEASE; GENOTYPING TECHNIQUES; HUMANS;

EID: 85014572880     PISSN: 14710056     EISSN: 14710064     Source Type: Journal    
DOI: 10.1038/nrg.2017.4     Document Type: Review

References (177)

1. de la Torre-Ubieta, L., Won, H., Stein, J. L. & Geschwind, D. H. Advancing the understanding of autism disease mechanisms through genetics. Nat. Med. 22, 345-361 (2016).
2. D'Gama, A. M. et al. Targeted DNA sequencing from autism spectrum disorder brains implicates multiple genetic mechanisms. Neuron 88, 910-917 (2015).
3. Ronemus, M., Iossifov, I., Levy, D. & Wigler, M. The role of de novo mutations in the genetics of autism spectrum disorders. Nat. Rev. Genet. 15, 133-141 (2014).
4. Buxbaum, J. D. Multiple rare variants in the etiology of autism spectrum disorders. Dialogues Clin. Neurosci. 11, 35-43 (2009).
5. Sanders, S. J. et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87, 1215-1233 (2015).
6. Crino, P. B., Nathanson, K. L. & Henske, E. P. The tuberous sclerosis complex. N. Engl. J. Med. 355, 1345-1356 (2006).
7. Kidd, S. A. et al. Fragile X syndrome: a review of associated medical problems. Pediatrics 134, 995-1005 (2014).
8. Cross-Disorder Group of the Psychiatric Genomics Consortium et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984-994 (2013).
9. Gaugler, T. et al. Most genetic risk for autism resides with common variation. Nat. Genet. 46, 881-885 (2014).
10. Klei, L. et al. Common genetic variants, acting additively, are a major source of risk for autism. Mol. Autism 3, 9 (2012).
11. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421-427 (2014).
12. Vorstman, J. A. et al. Using genetic findings in autism for the development of new pharmaceutical compounds. Psychopharmacology (Berl. ) 231, 1063-1078 (2014).
13. Vorstman, J. A. et al. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol. Psychiatry 11, 18-28 (2006).
14. Miller, D. T. 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. 86, 749-764 (2010).
15. Trakadis, Y. & Shevell, M. Microarray as a first genetic test in global developmental delay: a cost-effectiveness analysis. Dev. Med. Child Neurol. 53, 994-999 (2011).
16. Manning, M., Hudgins, L., Professional, P. & Guidelines, C. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet. Med. 12, 742-745 (2010).
17. Committee On Bioethics et al. Ethical and policy issues in genetic testing and screening of children. Pediatrics 131, 620-622 (2013).
18. Volkmar, F. et al. Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J. Am. Acad. Child Adolesc. Psychiatry 53, 237-257 (2014).
19. Bamshad, M. J. et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat. Rev. Genet. 12, 745-755 (2011).
20. Awadalla, P. et al. Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Am. J. Hum. Genet. 87, 316-324 (2010).
21. Besenbacher, S. et al. Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios. Nat. Commun. 6, 5969 (2015).
22. Veltman, J. A. & Brunner, H. G. De novo mutations in human genetic disease. Nat. Rev. Genet. 13, 565-575 (2012).
23. Zhang, F. & Lupski, J. R. Non-coding genetic variants in human disease. Hum. Mol. Genet. 24, R102-R110 (2015).
24. Yu, T. W. et al. Using whole-exome sequencing to identify inherited causes of autism. Neuron 77, 259-273 (2013).
25. Carter, M. T. & Scherer, S. W. Autism spectrum disorder in the genetics clinic: a review. Clin. Genet. 83, 399-407 (2013).
26. Yang, Y. et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 312, 1870-1879 (2014).
27. Gagan, J. & Van Allen, E. M. Next-generation sequencing to guide cancer therapy. Genome Med. 7, 80 (2015).
28. Basu S.N, Kollu, R. & Banerjee-Basu, S. AutDB: a gene reference resource for autism research. Nucleic Acids Res. 37, D832-D836 (2009).
29. Pinto, D. et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am. J. Hum. Genet. 94, 677-694 (2014).
30. Leppa, V. M. et al. Rare inherited and de novo CNVs reveal complex contributions to ASD risk in multiplex families. Am. J. Hum. Genet. 99, 540-554 (2016).
31. Cotney, J. et al. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat. Commun. 6, 6404 (2015).
32. Bernier, R. et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158, 263-276 (2014).
33. Krumm, N., O'Roak, B. J., Shendure, J. & Eichler, E. E. A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci. 37, 95-105 (2014).
34. Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216-221 (2014).
35. Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368-372 (2010).
36. Szatmari, P. et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat. Genet. 39, 319-328 (2007).
37. De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209-215 (2014).
38. Hormozdiari, F., Penn, O., Borenstein, E. & Eichler, E. E. The discovery of integrated gene networks for autism and related disorders. Genome Res. 25, 142-154 (2015).
39. Parikshak, N. N. et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155, 1008-1021 (2013).
40. Liu, L. et al. DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics. Mol. Autism 5, 22 (2014).
41. Willsey, A. J. et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155, 997-1007 (2013).
42. Parikshak, N. N., Gandal, M. J. & Geschwind, D. H. Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders. Nat. Rev. Genet. 16, 441-458 (2015).
43. Krishnan, A. et al. Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder. Nat. Neurosci. 19, 1454-1462 (2016).
44. Bailey, A. & Parr, J. Implications of the broader phenotype for concepts of autism. Novartis Found. Symp. 251, 26-35 (2003).
45. Moreno-De-Luca, A. et al. Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. Lancet Neurol. 12, 406-414 (2013).
46. Klaassen, P. et al. Explaining the variable penetrance of CNVs: parental intelligence modulates expression of intellectual impairment caused by the 22q11. 2 deletion. Am. J. Med. Genet. B Neuropsychiatr. Genet. 171, 790-796 (2016).
47. Lim, E. T. et al. Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron 77, 235-242 (2013).
48. Vorstman, J. A. et al. A double hit implicates DIAPH3 as an autism risk gene. Mol. Psychiatry 16, 442-451 (2011).
49. Zhao, X. et al. A unified genetic theory for sporadic and inherited autism. Proc. Natl Acad. Sci. USA 104, 12831-12836 (2007).
50. Schaaf, C. P. et al. Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Hum. Mol. Genet. 20, 3366-3375 (2011).
51. Heil, K. M. & Schaaf, C. P. The genetics of autism spectrum disorders-a guide for clinicians. Curr. Psychiatry Rep. 15, 334 (2013).
52. Gillberg, C. Autism and related behaviours. J. Intellect. Disabil. Res. 37, 343-372 (1993).
53. Kang, V., Wagner, G. C. & Ming, X. Gastrointestinal dysfunction in children with autism spectrum disorders. Autism Res. 7, 501-506 (2014).
54. Gesundheit, B. et al. Immunological and autoimmune considerations of autism spectrum disorders. J. Autoimmun. 44, 1-7 (2013).
55. Tilford, J. M. et al. Treatment for sleep problems in children with autism and caregiver spillover effects. J. Autism Dev. Disord. 45, 3613-3623 (2015).
56. Malhotra, D. & Sebat, J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148, 1223-1241 (2012).
57. Vorstman, J. A. & Ophoff, R. A. Genetic causes of developmental disorders. Curr. Opin. Neurol. 26, 128-136 (2013).
58. Grayton, H. M., Fernandes, C., Rujescu, D. & Collier, D. A. Copy number variations in neurodevelopmental disorders. Prog. Neurobiol. 99, 81-91 (2012).
59. Baasch, A. L. et al. Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities. Epilepsia 55, e25-e29 (2014).
60. Nakamura, K. et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 81, 992-998 (2013).
61. Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179-184 (2014).
62. Schwarz, N. et al. Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia. J. Neurol. 263, 334-343 (2016).
63. Glassford, M. R. et al. Novel features of 3q29 deletion syndrome: results from the 3q29 registry. Am. J. Med. Genet. A 170A, 999-1006 (2016).
64. Bruining, H. et al. Behavioral signatures related to genetic disorders in autism. Mol. Autism 5, 11 (2014).
65. Henderson, L. B. et al. The impact of chromosomal microarray on clinical management: a retrospective analysis. Genet. Med. 16, 657-664 (2014).
66. Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236-1241 (2015).
67. Clarke, T. K. et al. Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population. Mol. Psychiatry 21, 419-425 (2015).
68. Schendel, D. E. et al. Association of psychiatric and neurologic comorbidity with mortality among persons with autism spectrum disorder in a Danish population. JAMA Pediatr. 170, 243-250 (2016).
69. Hirvikoski, T. et al. Premature mortality in autism spectrum disorder. Br. J. Psychiatry 208, 232-238 (2016).
70. Croen, L. A. et al. The health status of adults on the autism spectrum. Autism 19, 814-823 (2015).
71. Smith, L. E., Barker, E. T., Seltzer, M. M., Abbeduto, L. & Greenberg, J. S. Behavioral phenotype of fragile X syndrome in adolescence and adulthood. Am. J. Intellect. Dev. Disabil. 117, 1-17 (2012).
72. van Rijn, S. et al. The social behavioral phenotype in boys and girls with an extra X chromosome (Klinefelter syndrome and Trisomy X): a comparison with autism spectrum disorder. J. Autism Dev. Disord. 44, 310-320 (2014).
73. Pride, N. A., Payne, J. M. & North, K. N. The impact of ADHD on the cognitive and academic functioning of children with NF1. Dev. Neuropsychol. 37, 590-600 (2012).
74. Sun, Y. M., Lu, C. & Wu, Z. Y. Spinocerebellar ataxia: relationship between phenotype and genotype-a review. Clin. Genet. 90, 305-314 (2016).
75. Kovacs, G. G. Molecular pathological classification of neurodegenerative diseases: turning towards precision medicine. Int. J. Mol. Sci. 17, E189 (2016).
76. Rapin, I. Classification of behaviorally defined disorders: biology versus the DSM. J. Autism Dev. Disord. 44, 2661-2666 (2014).
77. Licinio, J. & Wong, M. L. A novel conceptual framework for psychiatry: vertically and horizontally integrated approaches to redundancy and pleiotropism that co-exist with a classification of symptom clusters based on DSM-5. Mol. Psychiatry 18, 846-848 (2013).
78. Miller, F. A., Hayeems, R. Z. & Bytautas, J. P. What is a meaningful result? Disclosing the results of genomic research in autism to research participants. Eur. J. Hum. Genet. 18, 867-871 (2010).
79. Reiff, M. et al. Parents' perceptions of the usefulness of chromosomal microarray analysis for children with autism spectrum disorders. J. Autism Dev. Disord. 45, 3262-3275 (2015).
80. Gershon, E. S. & Alliey-Rodriguez, N. New ethical issues for genetic counseling in common mental disorders. Am. J. Psychiatry 170, 968-976 (2013).
81. Wood, C. L. et al. Evidence for ASD recurrence rates and reproductive stoppage from large UK ASD research family databases. Autism Res. 8, 73-81 (2015).
82. Werling, D. M. & Geschwind, D. H. Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins. Mol. Autism 6, 27 (2015).
83. Goin-Kochel, R. P., Abbacchi, A., Constantino, J. N. & Autism Genetic Resource Exchange Consortium. Lack of evidence for increased genetic loading for autism among families of affected females: a replication from family history data in two large samples. Autism 11, 279-286 (2007).
84. Constantino, J. N. Recurrence rates in autism spectrum disorders. JAMA 312, 1154-1155 (2014).
85. Messinger, D. S. et al. Early sex differences are not autism-specific: a Baby Siblings Research Consortium (BSRC) study. Mol. Autism 6, 32 (2015).
86. Shea, L., Newschaffer, C. J., Xie, M., Myers, S. M. & Mandell, D. S. Genetic testing and genetic counseling among Medicaid-enrolled children with autism spectrum disorder in 2001 and 2007. Hum. Genet. 133, 111-116 (2014).
87. Roesser, J. Diagnostic yield of genetic testing in children diagnosed with autism spectrum disorders at a regional referral center. Clin. Pediatr. (Phila. ) 50, 834-843 (2011).
88. Li, M. et al. Autism genetic testing information needs among parents of affected children: a qualitative study. Patient Educ. Couns. 99, 1011-1016 (2016).
89. Forero, D. A., Velez-van-Meerbeke, A., Deshpande, S. N., Nicolini, H. & Perry, G. Neuropsychiatric genetics in developing countries: current challenges. World J. Psychiatry 4, 69-71 (2014).
90. Cuccaro, M. L. et al. Genetic testing and corresponding services among individuals with autism spectrum disorder (ASD). Am. J. Med. Genet. A 164A, 2592-2600 (2014).
91. Baird, G., Douglas, H. R. & Murphy, M. S. Recognising and diagnosing autism in children and young people: summary of NICE guidance. BMJ 343, d6360 (2011).
92. Jeste, S. S. & Geschwind, D. H. Disentangling the heterogeneity of autism spectrum disorder through genetic findings. Nat. Rev. Neurol. 10, 74-81 (2014).
93. McCracken, J. T. et al. Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders. Pharmacogenomics J. 14, 295-302 (2014).
94. Correia, C. T. et al. Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions. Pharmacogenomics J. 10, 418-430 (2010).
95. Hoekstra, P. J. et al. Risperidone-induced weight gain in referred children with autism spectrum disorders is associated with a common polymorphism in the 5-hydroxytryptamine 2C receptor gene. J. Child Adolesc. Psychopharmacol. 20, 473-477 (2010).
96. Nurmi, E. L. et al. Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies. Transl Psychiatry 3, e274 (2013).
97. Waldman, S. A. & Terzic, A. Systems-based discovery advances drug development. Clin. Pharmacol. Ther. 93, 285-287 (2013).
98. Sztainberg, Y. & Zoghbi, H. Y. Lessons learned from studying syndromic autism spectrum disorders. Nat. Neurosci. 19, 1408-1417 (2016).
99. Fisher, J. A., Cottingham, M. D. & Kalbaugh, C. A. Peering into the pharmaceutical "pipeline": investigational drugs, clinical trials, and industry priorities. Soc. Sci. Med. 131, 322-330 (2015).
100. Downing, A. M. et al. A double-blind, placebo-controlled comparator study of LY2140023 monohydrate in patients with schizophrenia. BMC Psychiatry 14, 351 (2014).
101. Main, P. A., Angley, M. T., O'Doherty, C. E., Thomas, P. & Fenech, M. The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutr. Metab. (Lond. ) 9, 35 (2012).
102. Rojas, D. C. The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. J. Neural Transm. (Vienna) 121, 891-905 (2014).
103. Inglis, A., Koehn, D., McGillivray, B., Stewart, S. E. & Austin, J. Evaluating a unique, specialist psychiatric genetic counseling clinic: uptake and impact. Clin. Genet. 87, 218-224 (2015).
104. Pan, V., Yashar, B. M., Pothast, R. & Wicklund, C. Expanding the genetic counseling workforce: program directors' views on increasing the size of genetic counseling graduate programs. Genet. Med. 18, 842-849 (2016).
105. Gligorijevic, D. et al. Large-scale discovery of disease-disease and disease-gene associations. Sci. Rep. 6, 32404 (2016).
106. Gandal, M. J., Leppa, V., Won, H., Parikshak, N. N. & Geschwind, D. H. The road to precision psychiatry: translating genetics into disease mechanisms. Nat. Neurosci. 19, 1397-1407 (2016).
107. Coleman, K. J. et al. Validation of autism spectrum disorder diagnoses in large healthcare systems with electronic medical records. J. Autism Dev. Disord. 45, 1989-1996 (2015).
108. Burke, J. P. et al. Does a claims diagnosis of autism mean a true case? Autism 18, 321-330 (2014).
109. Beversdorf, D. Q. & Missouri Autism Summit Consortium. Phenotyping etiological factors, and biomarkers: toward precision medicine in autism spectrum disorders. J. Dev. Behav. Pediatr. 37, 659-673 (2016).
110. Knapp, M., Romeo, R. & Beecham, J. Economic cost of autism in the UK. Autism 13, 317-336 (2009).
111. Rehm, H. L. et al. ClinGen-the clinical genome resource. N. Engl. J. Med. 372, 2235-2242 (2015).
112. Bernier, R. et al. Clinical phenotype of the recurrent 1q21. 1 copy-number variant. Genet. Med. 18, 341-349 (2016).
113. Green Snyder, L. et al. Autism spectrum disorder, developmental and psychiatric features in 16p11. 2 duplication. J. Autism Dev. Disord. 46, 2734-2748 (2016).
114. Moreno-De-Luca, D. et al. Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts. Mol. Psychiatry 18, 1090-1095 (2012).
115. McDonald-McGinn, D. et al. 22q11. 2 deletion syndrome. Nat. Rev. Dis. Primers 1, 15071 (2015).
116. McCandless, S. E. & Committee on Genetics. Clinical report-health supervision for children with Prader-Willi syndrome. Pediatrics 127, 195-204 (2011).
117. McBride, K. L. et al. Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly. Autism Res. 3, 137-141 (2010).
118. Helsmoortel, C. et al. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat. Genet. 46, 380-384 (2014).
119. Cubells, J. F. et al. Pharmaco-genetically guided treatment of recurrent rage outbursts in an adult male with 15q13. 3 deletion syndrome. Am. J. Med. Genet. A. 155A, 805-810 (2011).
120. Glick, N. Dramatic reduction in self-injury in Lesch-Nyhan disease following S-adenosylmethionine administration. J. Inherit. Metab. Dis. 29, 687 (2006).
121. Chen, B. C. et al. Treatment of Lesch-Nyhan disease with S-adenosylmethionine: experience with five young Malaysians, including a girl. Brain Dev. 36, 593-600 (2014).
122. Moreno-De-Luca, D. et al. Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. Am. J. Hum. Genet. 87, 618-630 (2010).
123. Phelan, K. & McDermid, H. E. The 22q13. 3 deletion syndrome (Phelan-McDermid syndrome). Mol. Syndromol. 2, 186-201 (2012).
124. Warnell, F. et al. Designing and recruiting to UK autism spectrum disorder research databases: do they include representative children with valid ASD diagnoses? BMJ Open 5, e008625 (2015).
125. Pellicano, E., Dinsmore, A. & Charman, T. What should autism research focus upon? Community views and priorities from the United Kingdom. Autism 18, 756-770 (2014).
126. Wallace, S., Parr, J. R. & Hardy, A. One in a hundred: putting families at the heart of autism research. Autistica https: //www. Autistica. org. uk/wp-content/ uploads/2014/10/One-in-a-Hundred-Autisticas-Report. pdf (2013).
127. Parr, J. Understanding opinions about clinical genetic testing in ASD. AACAP+CACAP Joint Annual Meeting https: //aacap. confex. com/aacap/2011/webprogram/ Session7546. html (Toronto, 2011).
128. Sandin, S. et al. The familial risk of autism. JAMA 311, 1770-1777 (2014).
129. Haldeman-Englert, C. & Jewett, T. 1q21. 1 recurrent microdeletion. GeneReviews https: //www. ncbi. nlm. nih. gov/books/NBK52787/ (2015).
130. Mefford, H. C. et al. Recurrent rearrangements of chromosome 1q21. 1 and variable pediatric phenotypes. N. Engl. J. Med. 359, 1685-1699 (2008).
131. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232-236 (2008).
132. Digilio, M. C. et al. Congenital heart defects in recurrent reciprocal 1q21. 1 deletion and duplication syndromes: rare association with pulmonary valve stenosis. Eur. J. Med. Genet. 56, 144-149 (2013).
133. Dolcetti, A. et al. 1q21. 1 microduplication expression in adults. Genet. Med. 15, 282-289 (2013).
134. Berg, J. S., Potocki, L. & Bacino, C. A. Common recurrent microduplication syndromes: diagnosis and management in clinical practice. Am. J. Med. Genet. A. 152A, 1066-1078 (2010).
135. Talkowski, M. E. 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. 89, 551-563 (2011).
136. Mullegama, S. V., Alaimo, J. T., Chen, L. & Elsea, S. H. Phenotypic and molecular convergence of 2q23. 1 deletion syndrome with other neurodevelopmental syndromes associated with autism spectrum disorder. Int. J. Mol. Sci. 16, 7627-7643 (2015).
137. Falk, R. E. & Casas, K. A. Chromosome 2q37 deletion: clinical and molecular aspects. Am. J. Med. Genet. C Semin. Med. Genet. 145C, 357-371 (2007).
138. Fisch, G. S., Battaglia, A., Parrini, B., Youngblom, J. & Simensen, R. Cognitive-behavioral features of children with Wolf-Hirschhorn syndrome: preliminary report of 12 cases. Am. J. Med. Genet. C Semin. Med. Genet. 148C, 252-256 (2008).
139. Leroy, C. et al. The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients. Eur. J. Hum. Genet. 21, 602-612 (2012).
140. Willatt, L. et al. 3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome. Am. J. Hum. Genet. 77, 154-160 (2005).
141. Zweier, M. & Rauch, A. The MEF2C-related and 5q14. 3q15 microdeletion syndrome. Mol. Syndromol. 2, 164-170 (2012).
142. Ilari, R., Agosta, G. & Bacino, C. 5q14. 3 deletion neurocutaneous syndrome: contiguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C: a progressive disease. Am. J. Med. Genet. A 170A, 688-693 (2016).
143. Van der Aa, N. et al. Fourteen new cases contribute to the characterization of the 7q11. 23 microduplication syndrome. Eur. J. Med. Genet. 52, 94-100 (2009).
144. Velleman, S. L. & Mervis, C. B. Children with 7q11. 23 duplication syndrome: speech, language, cognitive, and behavioral characteristics and their implications for intervention. Perspect. Lang. Learn. Educ. 18, 108-116 (2011).
145. Mervis, C. B., Morris, C. A., Klein-Tasman, B. P., Velleman, S. L. & Osborne, L. R. 7q11. 23 duplication syndrome. GeneReviews https: //www. ncbi. nlm. nih. gov/ books/NBK327268/ (2015).
146. Mervis, C. B. et al. Duplication of GTF2I results in separation anxiety in mice and humans. Am. J. Hum. Genet. 90, 1064-1070 (2012).
147. Morris, C. A. et al. 7q11. 23 duplication syndrome: physical characteristics and natural history. Am. J. Med. Genet. A 167A, 2916-2935 (2015).
148. Baynam, G., Goldblatt, J. & Walpole, I. Deletion of 8p23. 1 with features of Cornelia de Lange syndrome and congenital diaphragmatic hernia and a review of deletions of 8p23. 1 to 8pter? A further locus for Cornelia de Lange syndrome. Am. J. Med. Genet. A. 146A, 1565-1570 (2008).
149. Rineer, S., Finucane, B. & Simon, E. W. Autistic symptoms among children and young adults with isodicentric chromosome 15. Am. J. Med. Genet. 81, 428-433 (1998).
150. Battaglia, A. The inv dup (15) or idic (15) syndrome (tetrasomy 15q). Orphanet. J. Rare Dis. 3, 30 (2008).
151. Thomas, J. A. et al. Genetic and clinical characterization of patients with an interstitial duplication 15q11-q13, emphasizing behavioral phenotype and response to treatment. Am. J. Med. Genet. A. 119A, 111-120 (2003).
152. Battaglia, A. The inv dup(15) or idic(15) syndrome: a clinically recognisable neurogenetic disorder. Brain Dev. 27, 365-369 (2005).
153. Kalsner, L. & Chamberlain, S. J. Prader-Willi, Angelman, and 15q11-q13 duplication syndromes. Pediatr. Clin. North Am. 62, 587-606 (2015).
154. Abdelmoity, A. T. et al. 15q11. 2 proximal imbalances associated with a diverse array of neuropsychiatric disorders and mild dysmorphic features. J. Dev. Behav. Pediatr. 33, 570-576 (2012).
155. Burnside, R. D. 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. 130, 517-528 (2011).
156. Cox, D. M. & Butler, M. G. The 15q11. 2 BP1-BP2 microdeletion syndrome: a review. Int. J. Mol. Sci. 16, 4068-4082 (2015).
157. Miller, D. T. et al. Microdeletion/duplication at 15q13. 2q13. 3 among individuals with features of autism and other neuropsychiatric disorders. J. Med. Genet. 46, 242-248 (2009).
158. Zufferey, F. et al. A 600 kb deletion syndrome at 16p11. 2 leads to energy imbalance and neuropsychiatric disorders. J. Med. Genet. 49, 660-668 (2012).
159. Steinman, K. J. et al. 16p11. 2 deletion and duplication: characterizing neurologic phenotypes in a large clinically ascertained cohort. Am. J. Med. Genet. A 170, 2943-2955 (2016).
160. McCarthy, S. E. et al. Microduplications of 16p11. 2 are associated with schiz ophrenia. Nat. Genet. 41, 1223-1227 (2009).
161. Ramalingam, A. et al. 16p13. 11 duplication is a risk factor for a wide spectrum of neuropsychiatric disorders. J. Hum. Genet. 56, 541-544 (2011).
162. Van Campenhout, S. et al. Microduplication 22q11. 2: a description of the clinical, developmental and behavioral characteristics during childhood. Genet. Couns. 23, 135-148 (2012).
163. Portnoi, M. F. Microduplication 22q11. 2: a new chromosomal syndrome. Eur. J. Med. Genet. 52, 88-93 (2009).
164. Stessman, H. A. et al. Disruption of POGZ is associated with intellectual disability and autism spectrum disorders. Am. J. Hum. Genet. 98, 541-552 (2016).
165. Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519, 223-228 (2015).
166. O'Roak, B. J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619-1622 (2012).
167. Hamdan, F. F. et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 10, e1004772 (2014).
168. Berryer, M. H. et al. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum. Mutat. 34, 385-394 (2013).
169. Hamdan, F. F. et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N. Engl. J. Med. 360, 599-605 (2009).
170. Lemke, J. R. et al. GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. Ann. Neurol. 75, 147-154 (2014).
171. Mohler, P. J. et al. Defining the cellular phenotype of "ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. Circulation 115, 432-441 (2007).
172. Hoyer, J. et al. Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. Am. J. Hum. Genet. 90, 565-572 (2012).
173. Santen, G. W., Clayton-Smith, J. & ARID1B-CSS consortium. The ARID1B phenotype: what we have learned so far. Am. J. Med. Genet. C Semin. Med. Genet. 166C, 276-289 (2014).
174. Yu, Y. et al. De novo mutations in ARID1B associated with both syndromic and non-syndromic short stature. BMC Genomics 16, 701 (2015).
175. Luco, S. M. et al. Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature. BMC Med. Genet. 17, 15 (2016).
176. Ji, J. et al. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. Eur. J. Hum. Genet. 23, 1473-1481 (2015).
177. Merner, N. et al. A de novo frameshift mutation in chromodomain helicase DNA-binding domain 8 (CHD8): a case report and literature review. Am. J. Med. Genet. A 170A, 1225-1235 (2016).