Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A framework for an evidence-based gene list relevant to autism spectrum disorder

Nature Reviews Genetics volume 21, pages 367–376 (2020)Cite this article

Abstract

Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overlap between three sets of genes considered to be associated with ASD susceptibility.
Fig. 2: Proposed pipeline.
Fig. 3: Systematic evaluation of quality of the ASD phenotype report.

References

  1. Lai, M. C., Lombardo, M. V. & Baron-Cohen, S. Autism. Lancet 383, 896–910 (2014).

    Article  PubMed  Google Scholar 

  2. Tammimies, K. et al. Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. JAMA 314, 895–903 (2015). This paper shows among a heterogeneous sample of children with ASD that the diagnostic yield was higher in children with more complex morphological phenotypes.

    Article  CAS  PubMed  Google Scholar 

  3. Feliciano, P. et al. Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes. NPJ Genom. Med. 4, 19 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Sanders, S. J. et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87, 1215–1233 (2015). This large study uses microarray and sequencing data to reveal strong evidence that de novo mutations are associated with ASD apart from the risk for ID.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. Shen, Y. et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 125, e727–e735 (2010).

    Article  PubMed  Google Scholar 

  7. Weiner, D. J. et al. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nat. Genet. 49, 978–985 (2017). This important study demonstrates that polygenic variation contributes additively to risk in individuals with ASD who carry a presumed penetrant de novo variant.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Barton, K. S. et al. Pathways from autism spectrum disorder diagnosis to genetic testing. Genet. Med. 20, 737–744 (2018).

    Article  PubMed  Google Scholar 

  9. Hoang, N., Cytrynbaum, C. & Scherer, S. W. Communicating complex genomic information: a counselling approach derived from research experience with autism spectrum disorder. Patient Educ. Couns. 101, 352–361 (2018).

    Article  PubMed  Google Scholar 

  10. Geschwind, D. H. & State, M. W. Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol. 14, 1109–1120 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Vorstman, J. A. S. et al. Autism genetics: opportunities and challenges for clinical translation. Nat. Rev. Genet. 18, 362–376 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. American Psychiatric Association & DSM Task Force. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) 5th edn (APA, 2013).

  13. Lord, C. & Bishop, S. L. Recent advances in autism research as reflected in DSM-5 criteria for autism spectrum disorder. Annu. Rev. Clin. Psychol. 11, 53–70 (2015). This review of advances in scientific knowledge about ASD uses DSM-5 diagnostic criteria as a framework for the discussion.

    Article  PubMed  Google Scholar 

  14. Sanders, S. J. Next-generation sequencing in autism spectrum disorder. Cold Spring Harb. Perspect. Med. 9, a026872 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ganna, A. et al. Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum. Am. J. Hum. Genet. 102, 1204–1211 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. He, Z., Xu, B., Buxbaum, J. & Ionita-Laza, I. A genome-wide scan statistic framework for whole-genome sequence data analysis. Nat. Commun. 10, 3018 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Werling, D. M. et al. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder. Nat. Genet. 50, 727–736 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hoang, N., Buchanan, J. A. & Scherer, S. W. Heterogeneity in clinical sequencing tests marketed for autism spectrum disorders. NPJ Genom. Med. 3, 27 (2018). This paper presents a comprehensive survey of sequencing tests for ASD that are primarily being marketed by commercial laboratories as adjuncts or follow-up to chromosomal microarrays.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Strande, N. T. et al. Evaluating the clinical validity of gene–disease associations: an evidence-based framework developed by the clinical genome resource. Am. J. Hum. Genet. 100, 895–906 (2017). This work presents the latest ClinGen classifications and framework recommendations to assess the strength of gene–disease relationships.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Smith, E. D. et al. Classification of genes: standardized clinical validity assessment of gene–disease associations aids diagnostic exome analysis and reclassifications. Hum. Mutat. 38, 600–608 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rehm, H. L. et al. ClinGen—the clinical genome resource. N. Engl. J. Med. 372, 2235–2242 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rivera-Munoz, E. A. et al. ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene-level specification of the ACMG/AMP guidelines for sequence variant interpretation. Hum. Mutat. 39, 1614–1622 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Angione, K., Gibbons, M. & Demarest, S. An objective method for evaluating next-generation sequencing panels. J. Child Neurol. 34, 139–143 (2018).

    Article  PubMed  Google Scholar 

  24. Pitini, E. et al. How is genetic testing evaluated? A systematic review of the literature. Eur. J. Hum. Genet. 26, 605–615 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sahin, M. & Sur, M. Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders. Science 350, aab3897 (2015).

    Article  PubMed  CAS  Google Scholar 

  26. Bale, T. L. et al. Early life programming and neurodevelopmental disorders. Biol. Psychiatry 68, 314–319 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gray, S. J. Gene therapy and neurodevelopmental disorders. Neuropharmacology 68, 136–142 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Gonzalez-Mantilla, A. J., Moreno-De-Luca, A., Ledbetter, D. H. & Martin, C. L. A cross-disorder method to identify novel candidate genes for developmental brain disorders. JAMA Psychiatry 73, 275–283 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  29. 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). This conceptual paper hypothesizes for the many ASD-relevant genes currently described as variably penetrant that, when the disorders encompassed by developmental brain dysfunction are considered as a group, the penetrance of these genes may approach 100%.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Srivastava, S. et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet. Med. 21, 2413–2421 (2019). This scoping review and meta-analysis leads to recommendations that exome sequencing should become a first-tier diagnostic test for NDDs, including ASD.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Carter, M. T. & Scherer, S. W. Autism spectrum disorder in the genetics clinic: a review. Clin. Genet. 83, 399–407 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Yuen, R. K. et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat. Med. 21, 185–191 (2015). This study finds that affected siblings can carry different ASD-relevant mutations, and when they do, they tend to demonstrate more clinical variability than those who share a variant.

    Article  CAS  PubMed  Google Scholar 

  33. Yuen, R. K. et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat. Neurosci. 20, 602–611 (2017). Using genome sequence and comprehensive annotation, this study finds that participants bearing mutations in ASD-relevant genes have lower adaptive ability than those who do not.

    Article  CAS  PubMed Central  Google Scholar 

  34. Satterstrom, F. K. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180, 568–584.e23 (2020). This large-scale exome sequencing study shows many ASD-relevant genes as conferring risk for ASD or for ASD with neurodevelopmental delay, based on whether a gene has a higher frequency of disruptive de novo variants in ASD or neurodevelopmental delay.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Matson, J. L. & Shoemaker, M. Intellectual disability and its relationship to autism spectrum disorders. Res. Dev. Disabil. 30, 1107–1114 (2009).

    Article  PubMed  Google Scholar 

  36. Skuse, D. H. Rethinking the nature of genetic vulnerability to autistic spectrum disorders. Trends Genet. 23, 387–395 (2007). This important discussion of the relationship between ASD and ID includes the idea that the presence of both characteristics in an individual increases the clinical ascertainment.

    Article  CAS  PubMed  Google Scholar 

  37. Shattuck, P. T. The contribution of diagnostic substitution to the growing administrative prevalence of autism in US special education. Pediatrics 117, 1028–1037 (2006).

    Article  PubMed  Google Scholar 

  38. Nevison, C. D. & Blaxill, M. Diagnostic substitution for intellectual disability: a flawed explanation for the rise in autism. J. Autism Dev. Disord. 47, 2733–2742 (2017).

    Article  PubMed  Google Scholar 

  39. Croen, L. A., Grether, J. K., Hoogstrate, J. & Selvin, S. The changing prevalence of autism in California. J. Autism Dev. Disord. 32, 207–215 (2002).

    Article  PubMed  Google Scholar 

  40. Ingram, D. H., Mayes, S. D., Troxell, L. B. & Calhoun, S. L. Assessing children with autism, mental retardation, and typical development using the playground observation checklist. Autism 11, 311–319 (2007).

    Article  PubMed  Google Scholar 

  41. Ventola, P. et al. Differentiating between autism spectrum disorders and other developmental disabilities in children who failed a screening instrument for ASD. J. Autism Dev. Disord. 37, 425–436 (2007).

    Article  PubMed  Google Scholar 

  42. Pedersen, A. L. et al. DSM criteria that best differentiate intellectual disability from autism spectrum disorder. Child Psychiatry Hum. Dev. 48, 537–545 (2017).

    Article  PubMed  Google Scholar 

  43. Mooney, E. L., Gray, K. M. & Tonge, B. J. Early features of autism: repetitive behaviours in young children. Eur. Child Adolesc. Psychiatry 15, 12–18 (2006).

    Article  PubMed  Google Scholar 

  44. Osterling, J. A., Dawson, G. & Munson, J. A. Early recognition of 1-year-old infants with autism spectrum disorder versus mental retardation. Dev. Psychopathol. 14, 239–251 (2002).

    Article  PubMed  Google Scholar 

  45. Baranek, G. T. Autism during infancy: a retrospective video analysis of sensory-motor and social behaviors at 9–12 months of age. J. Autism Dev. Disord. 29, 213–224 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Clifford, S. M. & Dissanayake, C. The early development of joint attention in infants with autistic disorder using home video observations and parental interview. J. Autism Dev. Disord. 38, 791–805 (2008).

    Article  PubMed  Google Scholar 

  47. Mitchell, S., Cardy, J. O. & Zwaigenbaum, L. Differentiating autism spectrum disorder from other developmental delays in the first two years of life. Dev. Disabil. Res. Rev. 17, 130–140 (2011).

    Article  PubMed  Google Scholar 

  48. Brereton, A. V., Tonge, B. J. & Einfeld, S. L. Psychopathology in children and adolescents with autism compared to young people with intellectual disability. J. Autism Dev. Disord. 36, 863–870 (2006).

    Article  PubMed  Google Scholar 

  49. Barrett, B. et al. Comparing service use and costs among adolescents with autism spectrum disorders, special needs and typical development. Autism 19, 562–569 (2015).

    Article  PubMed  Google Scholar 

  50. Weitlauf, A. S. et al. Therapies for children with autism spectrum disorder: behavioral interventions update (US Agency for Healthcare Research and Quality, 2014).

  51. Helbig, I. et al. The ClinGen Epilepsy Gene Curation Expert Panel—bridging the divide between clinical domain knowledge and formal gene curation criteria. Hum. Mutat. 39, 1476–1484 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  52. World Health Organization. International statistical classification of diseases and related health problems (WHO, 2004).

  53. Fernandez, B. A. & Scherer, S. W. Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach. Dialogues Clin. Neurosci. 19, 353–371 (2017).

    PubMed  PubMed Central  Google Scholar 

  54. Leblond, C. S. et al. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLOS Genet. 10, e1004580 (2014). This study of the SHANK1, SHANK2 and SHANK3 genes in ASD demonstrates that mutations are detected in the entire spectrum of autism with a gradient of severity in cognitive impairment.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Niarchou, M. et al. Psychiatric disorders in children with 16p11.2 deletion and duplication. Transl. Psychiatry 9, 8 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Weiss, L. A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Vorstman, J. A. et al. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. J. Am. Acad. Child Adolesc. Psychiatry 45, 1104–1113 (2006).

    Article  PubMed  Google Scholar 

  58. Fiksinski, A. M. et al. Understanding the pediatric psychiatric phenotype of 22q11.2 deletion syndrome. Am. J. Med. Genet. A 176, 2182–2191 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Soorya, L. et al. Prospective investigation of autism and genotype–phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol. Autism 4, 18 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bernier, R. et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158, 263–276 (2014). This next-generation sequencing study identifies disruptions in CHD8 to define a distinct ASD subtype and reveal comorbidities between brain development and enteric innervation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sanders, S. J. et al. A framework for the investigation of rare genetic disorders in neuropsychiatry. Nat. Med. 25, 1477–1487 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Frazier, T. W. et al. Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism. Mol. Psychiatry 20, 1132–1138 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Fernandez, B. A. et al. Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. J. Med. Genet. 47, 195–203 (2010).

    Article  PubMed  Google Scholar 

  66. D’Angelo, D. et al. Defining the effect of the 16p11.2 duplication on cognition, behavior, and medical comorbidities. JAMA Psychiatry 73, 20–30 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Ross, P. J. et al. Synaptic dysfunction in human neurons with autism-associated deletions in PTCHD1-AS. Biol. Psychiatry 87, 139–149 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  68. De Rubeis, S. & Buxbaum, J. D. Genetics and genomics of autism spectrum disorder: embracing complexity. Hum. Mol. Genet. 24, R24–R31 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Lim, E. T. et al. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat. Neurosci. 20, 1217–1224 (2017). This exome sequencing study identifies that somatic mutations constitute a significant proportion of de novo mutations and can contribute importantly to ASD phenotypes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lai, M. C., Baron-Cohen, S. & Buxbaum, J. D. Understanding autism in the light of sex/gender. Mol. Autism 6, 24 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Paaby, A. B. & Rockman, M. V. The many faces of pleiotropy. Trends Genet. 29, 66–73 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Vorstman, J. A. & Ophoff, R. A. Genetic causes of developmental disorders. Curr. Opin. Neurol. 26, 128–136 (2013).

    Article  PubMed  Google Scholar 

  73. Depienne, C. et al. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. J. Med. Genet. 47, 404–410 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Bassett, A. S. et al. Rare genome-wide copy number variation and expression of schizophrenia in 22q11.2 deletion syndrome. Am. J. Psychiatry 174, 1054–1063 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Pizzo, L. et al. Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants. Genet. Med. 21, 816–825 (2019).

    Article  CAS  PubMed  Google Scholar 

  76. An, J. Y. et al. Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science 362, eaat6576 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Garg, P. & Sharp, A. J. Screening for rare epigenetic variations in autism and schizophrenia. Hum. Mutat. 40, 952–961 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Andrews, S. V. et al. Case–control meta-analysis of blood DNA methylation and autism spectrum disorder. Mol. Autism 9, 40 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Hagerman, R., Au, J. & Hagerman, P. FMR1 premutation and full mutation molecular mechanisms related to autism. J. Neurodev. Disord. 3, 211–224 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Modabbernia, A., Velthorst, E. & Reichenberg, A. Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses. Mol. Autism 8, 13 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Grove, J. et al. Identification of common genetic risk variants for autism spectrum disorder. Nat. Genet. 51, 431–444 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Coe, B. P. et al. Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nat. Genet. 51, 106–116 (2019).

    Article  CAS  PubMed  Google Scholar 

  83. Jacquemont, S. et al. A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am. J. Hum. Genet. 94, 415–425 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Larsen, E. et al. A systematic variant annotation approach for ranking genes associated with autism spectrum disorders. Mol. Autism 7, 44 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Abrahams, B. S. et al. SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs). Mol. Autism 4, 36 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Hyman, S. L., Levy, S. E. & Myers, S. M., Council on Children with Disabilities, Section on Developmental & Behavioral Pediatrics. Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics 145, e20193447 (2020).

    Article  PubMed  Google Scholar 

  87. Iakoucheva, L. M., Muotri, A. R. & Sebat, J. Getting to the cores of autism. Cell 178, 1287–1298 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Clinical Genome Resource Gene Curation Working Group. Gene clinical validity curation process standard operating procedure. Version 7. Clinical Genome https://clinicalgenome.org/docs/summary-of-updates-to-the-clingen-gene-clinical-validity-curation-sop-version-7/ (2019).

  89. Robinson, E. B., Lichtenstein, P., Anckarsater, H., Happe, F. & Ronald, A. Examining and interpreting the female protective effect against autistic behavior. Proc. Natl Acad. Sci. USA 110, 5258–5262 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Pinto, D. et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am. J. Hum. Genet. 94, 677–694 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lionel, A. C. et al. Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes. Hum. Mol. Genet. 23, 2752–2768 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Woodbury-Smith, M. et al. Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes. NPJ Genom. Med. 2, 17 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Yu, T. W. et al. Using whole-exome sequencing to identify inherited causes of autism. Neuron 77, 259–273 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Rejeb, I. et al. First case report of Cohen syndrome in the Tunisian population caused by VPS13B mutations. BMC Med. Genet. 18, 134 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Daoud, H. et al. Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level. Biol. Psychiatry 66, 906–910 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Risi, S. et al. Combining information from multiple sources in the diagnosis of autism spectrum disorders. J. Am. Acad. Child Adolesc. Psychiatry 45, 1094–1103 (2006).

    Article  PubMed  Google Scholar 

  98. Wang, T. et al. De novo genic mutations among a Chinese autism spectrum disorder cohort. Nat. Commun. 7, 13316 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Li, J. et al. Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Mol. Psychiatry 22, 1282–1290 (2017).

    Article  CAS  PubMed  Google Scholar 

  100. Sato, D. et al. SHANK1 deletions in males with autism spectrum disorder. Am. J. Hum. Genet. 90, 879–887 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhang, L. et al. A promoter variant in ZNF804A decreasing its expression increases the risk of autism spectrum disorder in the Han Chinese population. Transl. Psychiatry 9, 31 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Gouder, L. et al. Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations. Sci. Rep. 9, 94 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Khalil, R. et al. PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features. Am. J. Med. Genet. B Neuropsychiatr. Genet. 177, 736–745 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Pascolini, G. et al. Autism spectrum disorder in a patient with a genomic rearrangement that only involves the EPHA5 gene. Psychiatr. Genet. 29, 86–90 (2019).

    Article  CAS  PubMed  Google Scholar 

  105. O’Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Manning, M. A. et al. Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum. Pediatrics 114, 451–457 (2004).

    Article  PubMed  Google Scholar 

  107. 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 170, 1225–1235 (2016).

    Article  CAS  Google Scholar 

  108. Imaizumi, T., Kumakura, A., Yamamoto-Shimojima, K., Ondo, Y. & Yamamoto, T. Identification of a rare homozygous SZT2 variant due to uniparental disomy in a patient with a neurodevelopmental disorder. Intractable Rare Dis. Res. 7, 245–250 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

C.P.S. is supported by CDMRP Grant AR160154, the Foundation for Prader-Willi Research, the NR2F1 Foundation and the USP7 Foundation. K.A.D. is supported by the Boston Children’s Hospital Neuroscience Clinical Cluster grant. E.H.C. is supported by National Institute of Mental Health (NIMH) grant R01MH110920. P.S. is supported by Canadian Institutes of Health Research (CIHR) funding. S.W.S. is supported by the GlaxoSmithKline–CIHR Endowed Chair in Genome Sciences at the Hospital for Sick Children and University of Toronto. J.A.S.V. is funded by NIMH grant 1U01MH119741–01 and CIHR.

Author information

Authors and Affiliations

  1. Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

    Christian P. Schaaf

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Christian P. Schaaf & Chun-An Chen

  3. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

    Christian P. Schaaf

  4. Neuroscience Paris Seine, Institut de Biologie Paris Seine, Sorbonne Université, INSERM, CNRS, Paris, France

    Catalina Betancur

  5. The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada

    Ryan K. C. Yuen, Janet A. Buchanan, Ny Hoang, Jennifer Howe, Christian R. Marshall, Olivia Rennie, Stephen W. Scherer & Jacob A. S. Vorstman

  6. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Ryan K. C. Yuen & Stephen W. Scherer

  7. Population Health Science Institute, Sir James Spence Institute, Newcastle University, Royal Victoria Infirmary, Newcastle, UK

    Jeremy R. Parr

  8. Institute of Child Health, University College London, London, UK

    David H. Skuse

  9. Department of Psychiatry & Neuropsychiatric Genetics Research Group, School of Medicine, The Trinity Centre for Health Sciences, Trinity College Dublin, Dublin, Ireland

    Louise Gallagher

  10. Department of Psychiatry and Behavioral Sciences, University of Washington, Center for Child Health, Behavior, and Disabilities, Seattle, WA, USA

    Raphael A. Bernier

  11. Children’s Autism Center, Seattle, WA, USA

    Raphael A. Bernier

  12. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum

  13. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum

  14. Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Kira A. Dies

  15. Montreal Neurological Institute, Azrieli Centre for Autism Research, McGill University, Montreal, QC, Canada

    Mayada Elsabbagh

  16. Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust & Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK

    Helen V. Firth

  17. Autism Speaks, Cleveland, OH, USA

    Thomas Frazier

  18. CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada

    Jacques L. Michaud

  19. Department of Psychiatry, Hospital for Sick Children, Toronto, ON, Canada

    Peter Szatmari & Jacob A. S. Vorstman

  20. Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada

    Peter Szatmari

  21. Department of Pediatrics (in Medicine), Columbia University Medical Center, New York, NY, USA

    Wendy K. Chung

  22. Institute of Psychiatry, King’s College London, London, UK

    Patrick F. Bolton

  23. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    Edwin H. Cook

  24. McLaughlin Centre, University of Toronto, Toronto, ON, Canada

    Stephen W. Scherer

  25. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Jacob A. S. Vorstman

Authors
  1. Christian P. Schaaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catalina Betancur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryan K. C. Yuen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeremy R. Parr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David H. Skuse
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Louise Gallagher
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Raphael A. Bernier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Janet A. Buchanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joseph D. Buxbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chun-An Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kira A. Dies
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mayada Elsabbagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Helen V. Firth
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Thomas Frazier
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ny Hoang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jennifer Howe
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Christian R. Marshall
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Jacques L. Michaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Olivia Rennie
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Peter Szatmari
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Wendy K. Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Patrick F. Bolton
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Edwin H. Cook
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Stephen W. Scherer
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Jacob A. S. Vorstman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.P.S., C.B., N.H., J.H., O.R. and J.A.S.V. researched the literature. C.P.S., C.B., R.K.C.Y., J.R.P., D.H.S., L.G., R.A.B., J.A.B., J.D.B., C.-A.C., K.A.D., M.E., H.V.F., T.F., N.H., J.H., C.M., J.L.M., P.S., W.K.C., P.F.B., E.H.C., S.W.S. and J.A.S.V. provided substantial contributions to discussions of the content. C.P.S., C.B., N.H., S.W.S. and J.A.S.V. wrote the article. C.P.S., C.B., R.K.C.Y., J.R.P., D.H.S., L.G., R.A.B., J.A.B., J.D.B., K.A.D., M.E., H.V.F., T.F., N.H., J.H., C.M., J.L.M., P.S., W.K.C., P.F.B., E.H.C., S.W.S. and J.A.S.V. reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Stephen W. Scherer or Jacob A. S. Vorstman.

Ethics declarations

Competing interests

H.V.F. is a section editor for Genetics for UpToDate. W.K.C. declares that she is part of the Regeneron Genetics Center Scientific Advisory Board. S.W.S. declares that he is part of scientific advisory committees and/or has intellectual property licensed to Deep Genomics, Population Bio, Lineagen and Athena Diagnostics.

Additional information

Peer review information

Nature Reviews Genetics thanks D. Amaral and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schaaf, C.P., Betancur, C., Yuen, R.K.C. et al. A framework for an evidence-based gene list relevant to autism spectrum disorder. Nat Rev Genet 21, 367–376 (2020). https://doi.org/10.1038/s41576-020-0231-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41576-020-0231-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing