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Cited by 640Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalities

Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

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Fu, Jack M., Satterstrom, F. Kyle, Peng, Minshi, Brand, Harrison, Collins, Ryan L., Dong, Shan, Wamsley, Brie, Klei, Lambertus +112 more·2022·Nature Genetics
DOI 10.1038/s41588-022-01104-0PMC PMC9653013

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Abstract

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

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  • Four heterozygous missense CYFIP1 variants were identified in patients with autism spectrum disorder, including a common variant p.Gly820Ser and three rare variants p.Asp544Asn, p.Met956Arg, and p.Ala1025Thr.

    “Four heterozygous missense CYFIP1 variants were identified in patients with ASD, including a common variant, p.Gly820Ser113 (Table 2l), and three rare variants, p.Asp544Asn, p.Met956Arg and p.Ala1025Thr114 (Table 2m).”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [114]

    The Results section, “Patterns of rare coding variants in ASD” (page unavailable), reports missense variants in ASD generally, but does not identify CYFIP1 variants. Searches for CYFIP1 and all four named substitutions found no passage in our copy confirming their identities, heterozygosity, or common versus rare status. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • An initiation codon variant c.2T > A (p.Met1?) and a regulatory sequence variant c.*135T > C in BRK1 were identified in two patients with autism spectrum disorder.

    “An initiation codon variant c.2T > A, p.Met1? and a regulatory sequence variant, c. *135T > C in BRK1 was identified in two patients with autism spectrum disorder114, but the functional consequences of the variants remain to be studied (Table 2z).”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [114]

    The Results section discusses rare variants in autism spectrum disorder, but the passages in our copy do not identify either specified BRK1 variant or report their occurrence in two patients. Searches for BRK1 and the variant notation found no passage addressing that specific claim; no page numbers were available for the retrieved passages. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • Next-generation sequencing identified one intronic, two missense, and two nonsense variants in NCKAP1L in autism patients.

    “Next-generation sequencing identified one intronic114, two missense133,134, and two nonsense variants in autism patients104,114, and the functional consequences of these variants remain to be established (Table 2u).”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [114]

    The Results section reports exome sequencing and protein-truncating and missense variants in ASD cohorts, but it does not identify NCKAP1L or give the claimed variant counts. Searches for NCKAP1L and for the intronic, missense, and nonsense variant combination found no passage in our copy establishing the NCKAP1L variants attributed to this source. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • Two missense variants in ABI1, c.584C > T (p.Thr195Ile) and c.1238A > C (p.Glu413Ala), were found in patients with myelomeningocele and autism spectrum disorder, respectively.

    “Additionally, two missense variants, c.584C > T, p.Thr195Ile, and c.1238A > C, p.Glu413Ala, in ABI1 were found in patients with myelomeningocele (spina bifida)138 and ASD104,114, respectively.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [114]

    The citation to this paper is attached to the ASD finding, not the myelomeningocele finding cited separately. The Results section reports damaging missense variants in ASD cohorts, but our copy does not identify the ABI1 c.1238A > C (p.Glu413Ala) variant in an ASD patient. Searches for ABI1, Glu413Ala, and the variant notation found no matching passage. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Cites

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Authors
Fu, J. M., Satterstrom, F. K., Peng, M., Brand, H., Collins, R. L., Dong, S., Wamsley, B., Klei, L., Wang, L., Hao, S. P., Stevens, C. R., Cusick, C., Babadi, M., Banks, E., Collins, B., Dodge, S., Gabriel, S. B., Gauthier, L., Lee, S. K., Liang, L., Ljungdahl, A., Mahjani, B., Sloofman, L., Smirnov, A. N., Barbosa, M., Betancur, C., Brusco, A., Chung, B. H. Y., Cook, E. H., Cuccaro, M. L., Domenici, E., Ferrero, G. B., Gargus, J. J., Herman, G. E., Hertz-Picciotto, I., Maciel, P., Manoach, D. S., Passos-Bueno, M. R., Persico, A. M., Renieri, A., Sutcliffe, J. S., Tassone, F., Trabetti, E., Campos, G., Cardaropoli, S., Carli, D., Chan, M. C. Y., Fallerini, C., Giorgio, E., Girardi, A. C., Hansen-Kiss, E., Lee, S. L., Lintas, C., Ludena, Y., Nguyen, R., Pavinato, L., Pericak-Vance, M., Pessah, I. N., Schmidt, R. J., Smith, M., Costa, C. I. S., Trajkova, S., Wang, J. Y. T., Yu, M. H. C., The Autism Sequencing Consortium (ASC), Aleksic, B., Artomov, M., Benetti, E., Biscaldi-Schafer, M., Børglum, A. D., Carracedo, A., Chiocchetti, A. G., Coon, H., Doan, R. N., Fernández-Prieto, M., Freitag, C. M., Gerges, S., Guter, S., Hougaard, D. M., Hultman, C. M., Jacob, S., Kaartinen, M., Kolevzon, A., Kushima, I., Lehtimäki, T., Rizzo, C. L., Maltman, N., Manara, M., Meiri, G., Menashe, I., Miller, J., Minshew, N., Mosconi, M., Ozaki, N., Palotie, A., Parellada, M., Puura, K., Reichenberg, A., Sandin, S., Scherer, S. W., Schlitt, S., Schmitt, L., Schneider-Momm, K., Siper, P. M., Suren, P., Sweeney, J. A., Teufel, K., del Pilar Trelles, M., Weiss, L. A., Yuen, R., Broad Institute Center for Common Disease Genomics (Broad-CCDG), iPSYCH-BROAD Consortium, Cutler, D. J., De Rubeis, S., Buxbaum, J. D., Daly, M. J., Devlin, B., Roeder, K., Sanders, S. J., & Talkowski, M. E.
Affiliations
  • Broad Institute (US)
  • Carnegie Mellon University (US)
  • University of California, San Francisco (US)
  • University of California, Los Angeles (US)
  • University of Pittsburgh (US)
  • Harvard University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Karolinska Institutet (SE)
  • Centre National de la Recherche Scientifique (FR)
  • Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
  • Duchess of Kent Children's Hospital (CN)
  • University of Illinois Chicago (US)
  • University of Miami (US)
  • University of Trento (IT)
  • University of Turin (IT)
  • University of California, Irvine (US)
  • Nationwide Children's Hospital (US)
  • University of Messina (IT)
  • University of Siena (IT)
  • Vanderbilt University (US)
  • University of California, Davis (US)
  • University of Verona (IT)
  • Universidade de São Paulo (BR)
  • Università Campus Bio-Medico (IT)
  • Goethe University Frankfurt (DE)
  • Lundbeck Foundation (DK)
  • Nagoya University (JP)
  • University of Utah (US)
  • Boston Children's Hospital (US)
  • Tampere University (FI)
  • Ben-Gurion University of the Negev (IL)
  • Children's Hospital of Philadelphia (US)
  • University of Kansas (US)
  • University of Helsinki (FI)
  • Universidad Complutense de Madrid (ES)
  • Hospital for Sick Children (CA)
  • University of Cincinnati (US)
  • Emory University (US)
Corresponding author
Roeder, Kathryn
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2022-08-18
Volume
54
Issue
9
Pages
1320-1331
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-022-01104-0
PMC
PMC9653013
OpenAlex
W4293068820
Cited by
640
References
26
Citations by year
2026: 183 · 2025: 148 · 2024: 196 · 2023: 87 · 2022: 25
FWCI
16.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • Iris (University of Trento) (submittedVersion)
  • Use Siena air (University of Siena) (submittedVersion, other-oa)
Funders
  • Simons Foundation (573206, 606362, 608540, 575097, 574598, 647371)
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (MH115957, MH111661, MH100233, MH111660, MH057881, MH109900, MH100027)
  • U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (HG008895)
  • U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD081256)
  • Autism Speaks (11852)
  • National Science Foundation (2017240332)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
autism spectrum disorder, truncating mutations, missense mutations, copy number variation, de novo mutations, developmental delay, genetic architecture, neuronal cell types, schizophrenia, shared genetic pathways, gene prioritization
MeSH terms
Autism Spectrum Disorder, Autistic Disorder, Humans, Mutation, Genetic Predisposition to Disease, DNA Copy Number Variations

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