The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.
Recessive gene disruptions in autism spectrum disorder
Open accessAbstract
Autism spectrum disorder (ASD) affects up to 1 in 59 individuals 1. Genome-wide association and large-scale sequencing studies strongly implicate both common variants 2-4 and rare de novo variants 5-10 in ASD. Recessive mutations have also been implicated 11-14 but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to approximately 5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes (CA2, DDHD1, NSUN2, PAH, RARB, ROGDI, SLC1A1, USH2A) as well as other genes not previously implicated in ASD including FEV (FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“In addition to dominant mutations, biallelic recessive mutations are descriptively more prevalent in autistic females than in autistic males237.”
From Sex and gender in neurodevelopmental conditions (2023) · cites this paper as [237]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data
Wang, K., Li, M., & Hakonarson, H. H. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq603 · Cited by 14,724
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587
Self-citationGlutamate neurotoxicity and diseases of the nervous system
Choi, D. W. (1988) · Neuron · doi:10.1016/0896-6273(88)90162-6 · Cited by 8,188
SIFT: predicting amino acid changes that affect protein function
Ng, P. C. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg509 · Cited by 6,601
Baio, J., Wiggins, L., Christensen, D. L., Maenner, M. J., Daniels, J., Warren, Z., Kurzius-Spencer, M., Zahorodny, W., Robinson, C., Rosenberg, et al. (2018) · MMWR. Surveillance Summaries · doi:10.15585/mmwr.ss6706a1 · Cited by 6,078
Browning, S. R., & Browning, B. L. (2007) · The American Journal of Human Genetics · doi:10.1086/521987 · Cited by 3,217
MutationTaster evaluates disease-causing potential of sequence alterations
Schwarz, J. M., Rödelsperger, C., Schuelke, M., & Seelow, D. (2010) · Nature Methods · doi:10.1038/nmeth0810-575 · Cited by 2,975
Synaptic, transcriptional and chromatin genes disrupted in autism
Study, T. D., De Rubeis, S., Autism, H. M. C. F., UK10K Consortium, The Autism Sequencing Consortium, He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Ercument Cicek, A., et al. (2014) · Nature · doi:10.1038/nature13772 · Cited by 2,746
Self-citationDe novo mutations revealed by whole-exome sequencing are strongly associated with autism
Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., Ercan-Sencicek, A. G., DiLullo, N. M., Parikshak, N. N., Stein, J. L., et al. (2012) · Nature · doi:10.1038/nature10945 · Cited by 2,084
Predicting the functional impact of protein mutations: application to cancer genomics
Reva, B. A., Antipin, Y., & Sander, C. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr407 · Cited by 2,046
Localization of neuronal and glial glutamate transporters
Rothstein, J. D., Martin, L. J., Levey, A. I., Dykes‐Hoberg, M., Jin, L., Wu, D. M., Nash, N. R., & Kuncl, R. W. (1994) · Neuron · doi:10.1016/0896-6273(94)90038-8 · Cited by 1,703
Association between Microdeletion and Microduplication at 16p11.2 and Autism
Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R., Saemundsen, E., Stefansson, H., Ferreira, M. A. R., Green, T., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa075974 · Cited by 1,666
Self-citationDe Novo Gene Disruptions in Children on the Autistic Spectrum
Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., Yamrom, B., Lee, Y.-H., Narzisi, G., Leotta, A., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.04.009 · Cited by 1,446
Naarden Braun, K. V., Lopez, M., White, T., et al. (2023) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/y3kk-5x30 · Cited by 1,381
Stenson, P. D., Mort, M. E., Ball, E. V., Evans, K., Hayden, M., Heywood, S., Hussain, M., Phillips, A. D., & Cooper, D. N. (2017) · Human Genetics · doi:10.1007/s00439-017-1779-6 · Cited by 1,363
Most genetic risk for autism resides with common variation
Gaugler, T., Klei, L., Sanders, S. J., Bodea, C. A., Goldberg, A. P., Lee, A. B., Mahajan, M., Manaa, D., Pawitan, Y., Reichert, J., et al. (2014) · Nature Genetics · doi:10.1038/ng.3039 · Cited by 1,239
Self-citationThe spectrum of behaviors influenced by serotonin
Lucki, I. (1998) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00139-5 · Cited by 1,179
Identification of deleterious mutations within three human genomes
Chun, S., & Fay, J. C. (2009) · Genome Research · doi:10.1101/gr.092619.109 · Cited by 1,049
Betancur, C. (2011) · Brain Research · doi:10.1016/j.brainres.2010.11.078 · Cited by 954
Self-citationIdentifying autism loci and genes by tracing recent shared ancestry
Morrow, E. M., Yoo, S.-Y., Flavell, S. W., Kim, T.-K., Lin, Y., Hill, R. S., Mukaddes, N. M., Balkhy, S., Gascon, G., Hashmi, A., et al. (2008) · Science · doi:10.1126/science.1157657 · Cited by 737
Self-citationRare de novo and transmitted copy-number variation in autistic spectrum disorders
Levy, D., Ronemus, M., Yamrom, B., Lee, Y.-H., Leotta, A., Kendall, J., Marks, S., Lakshmi, B., Pai, D., Ye, K., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.015 · Cited by 712
Characterising and Predicting Haploinsufficiency in the Human Genome
Huang, N., Lee, I., Marcotte, E. M., & Hurles, M. E. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001154 · Cited by 659
Jacquemont, S., Coe, B. P., Hersch, M., Duyzend, M. H., Krumm, N., Bergmann, S., Beckmann, J. S., Rosenfeld, J. A., & Eichler, E. E. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.02.001 · Cited by 605
Excess of rare, inherited truncating mutations in autism
Krumm, N., Turner, T. N., Baker, C., Vives, L., Mohajeri, K., Witherspoon, K., Raja, A., Coe, B. P., Stessman, H. A., He, Z.-X., et al. (2015) · Nature Genetics · doi:10.1038/ng.3303 · Cited by 587
The serotonin system in autism spectrum disorder: From biomarker to animal models
Muller, C. L., Anacker, A. M. J., & Veenstra-VanderWeele, J. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2015.11.010 · Cited by 531
Examining and interpreting the female protective effect against autistic behavior
Robinson, E. B., Lichtenstein, P., Anckarsäter, H., Happé, F., & Ronald, A. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1211070110 · Cited by 531
iPSYCH-Broad Autism Group, Weiner, D. J., Psychiatric Genomics Consortium Autism Group, Wigdor, E. M., Ripke, S., Walters, R. K., Kosmicki, J. A., Grove, J., Samocha, K. E., Goldstein, J. I., et al. (2017) · Nature Genetics · doi:10.1038/ng.3863 · Cited by 516
Self-citationHendricks, T. J., Fyodorov, D., Wegman, L. J., Lelutiu, N. B., Pehek, E. A., Yamamoto, B., Silver, J., Weeber, E., Sweatt, J., & Deneris, E. S. (2003) · Neuron · doi:10.1016/s0896-6273(02)01167-4 · Cited by 486
Using Whole-Exome Sequencing to Identify Inherited Causes of Autism
Yu, T. W., Chahrour, M. H., Coulter, M. E., Jiralerspong, S., Okamura-Ikeda, K., Ataman, B., Schmitz-Abe, K., Harmin, D. A., Adli, M., Malik, A. N., et al. (2013) · Neuron · doi:10.1016/j.neuron.2012.11.002 · Cited by 442
Self-citationThe role of de novo mutations in the genetics of autism spectrum disorders
Ronemus, M., Iossifov, I., Levy, D., & Wigler, M. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3585 · Cited by 390
Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population
iPSYCH-SSI-Broad Autism Group, Robinson, E. B., St Pourcain, B., Anttila, V., Kosmicki, J. A., Bulik-Sullivan, B., Grove, J., Maller, J., Samocha, K. E., Sanders, S. J., et al. (2016) · Nature Genetics · doi:10.1038/ng.3529 · Cited by 367
Self-citationPeghini, P., Janzen, J., & Stoffel, W. (1997) · The EMBO Journal · doi:10.1093/emboj/16.13.3822 · Cited by 343
Hendricks, T. J., Francis, N. J., Fyodorov, D. V., & Deneris, E. S. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-23-10348.1999 · Cited by 300
Lim, E. T., Raychaudhuri, S., Sanders, S. J., Stevens, C., Sabo, A., MacArthur, D. G., Neale, B. M., Kirby, A., Ruderfer, D. M., Fromer, M., et al. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.029 · Cited by 266
Self-citationDiamond, J. S. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-21-08328.2001 · Cited by 258
Neuronal Glutamate Uptake Contributes to GABA Synthesis and Inhibitory Synaptic Strength
Mathews, G. C., & Diamond, J. S. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-06-02040.2003 · Cited by 204
Buxbaum, J. D., Daly, M. J., Devlin, B., Lehner, T., Roeder, K., & State, M. W. (2012) · Neuron · doi:10.1016/j.neuron.2012.12.008 · Cited by 194
Self-citationPet-1 is required across different stages of life to regulate serotonergic function
Liu, C., Maejima, T., Wyler, S. C., Casadesús, G., Herlitze, S., & Deneris, E. S. (2010) · Nature Neuroscience · doi:10.1038/nn.2623 · Cited by 183
Yu, T. W., Lim, E. T., Stevens, C. R., Gabriel, S., Chahrour, M. H., Ataman, B., Coulter, M. E., Hill, R. S., Schubert, C. R., Greenberg, M. E., et al. (2012) · Digital Access to Scholarship at Harvard (DASH) (Harvard University) · Cited by 179
Self-citationScimemi, A., Tian, H., & Diamond, J. S. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4845-09.2009 · Cited by 169
Bailey, C. G., Ryan, R. M., Thoeng, A. D., Ng, C., King, K., Vanslambrouck, J. M., Auray-Blais, C., Vandenberg, R. J., Bröer, S., & Rasko, J. E. J. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44474 · Cited by 162
Nieoullon, A. L., Canolle, B., Masmejean, F., Guillet, B. A., Pisano, P. S., & Lortet, S. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03978.x · Cited by 160
Chahrour, M. H., Yu, T. W., Lim, E. T., Ataman, B., Coulter, M. E., Hill, R. S., Stevens, C. R., Schubert, C. R., ARRA Autism Sequencing Collaboration, Greenberg, M. E., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002635 · Cited by 125
Self-citationThe Hippo Pathway Regulates Neuroblasts and Brain Size in Drosophila melanogaster
Poon, C. L. C., Mitchell, K. A., Kondo, S., Cheng, L. Y., & Harvey, K. F. (2016) · Current Biology · doi:10.1016/j.cub.2016.02.009 · Cited by 113
ERAP140, a Conserved Tissue-Specific Nuclear Receptor Coactivator
Shao, W., Halachmi, S., & Brown, M. A. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.10.3358-3372.2002 · Cited by 104
Blaker, A. L., Gupta, S. K., McCammon, J. M., Rienzo, G. D., & Sive, H. L. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.009944 · Cited by 92
Enabling research with human embryonic and fetal tissue resources
Gerrelli, D., Lisgo, S., Copp, A. J., & Lindsay, S. (2015) · Development · doi:10.1242/dev.122820 · Cited by 89
Changes in the expression of the glutamate transporter EAAT3/EAAC1 in health and disease
Bianchi, M. G., Bardelli, D., Chiu, M., & Bussolati, O. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1484-0 · Cited by 81
Teijema, H. L., van Gelderen, H. H., Giesberts, M. A. H., & de Angulo, L. (1974) · Metabolism · doi:10.1016/0026-0495(74)90108-5 · Cited by 70
Kerwin, J. M., Yang, Y., Merchán, P., Sarma, S., Thompson, J., Wang, X., Sandoval, J. E., Puelles, L., Baldock, R., & Lindsay, S. (2010) · Journal of Anatomy · doi:10.1111/j.1469-7580.2010.01290.x · Cited by 53
Cao, H., Yin, X., Cao, Y., Jin, Y., Wang, S., Kong, Y., Chen, Y., Gao, J., Heller, S., & Xu, Z. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056516 · Cited by 38
The Ets transcription factor Fev is specifically expressed in the human central serotonergic neurons
Maurer, P., Rorive, S., d’Exaerde, A. D. K., Schiffmann, S. N., Salmon, I. J., & de Launoit, Y. (2004) · Neuroscience Letters · doi:10.1016/j.neulet.2003.12.086 · Cited by 36
Stafford, M. M., Brown, M. N., Mishra, P., Stanwood, G. D., & Mathews, G. C. (2009) · Hippocampus · doi:10.1002/hipo.20600 · Cited by 34
Iyo, A. H., Porter, B., Deneris, E. S., & Austin, M. C. (2005) · Synapse · doi:10.1002/syn.20178 · Cited by 28
Park, S. M., Littleton, J. T., Park, H. R., & Lee, J. (2016) · Experimental Neurobiology · doi:10.5607/en.2016.25.1.33 · Cited by 27
Lee, S., Park, S., & Zuo, Z. (2011) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.2011.01404.x · Cited by 26
Dicarboxylic aminoaciduria associated with mental retardation
Swarna, M., Rao, D. N., & Reddy, P. P. (1989) · Human Genetics · doi:10.1007/bf00291178 · Cited by 25
Ross, J. R., Porter, B. E., Buckley, P. T., Eberwine, J. H., & Robinson, M. B. (2010) · Neurochemistry International · doi:10.1016/j.neuint.2010.12.012 · Cited by 22
Cheng, Y.-Z., Eley, L., Hynes, A.-M., Overman, L. M., Simms, R. J., Barker, A., Dawe, H. R., Lindsay, S., & Sayer, J. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044975 · Cited by 16
Self-citation
Cited by
Sorted by citations
Fu, J. M., Satterstrom, F. K., Peng, M., Brand, H., Collins, R. L., Dong, S., Wamsley, B., Klei, L., Wang, L., Hao, S. P., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01104-0 · Cited by 640
Self-citationGenomic architecture of autism from comprehensive whole-genome sequence annotation
Trost, B., Thiruvahindrapuram, B., Chan, A. J. S., Engchuan, W., Higginbotham, E. J., Howe, J., Loureiro, L. O., Reuter, M. S., Roshandel, D., Whitney, J., et al. (2022) · Cell · doi:10.1016/j.cell.2022.10.009 · Cited by 287
Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications
Jiang, C.-C., Lin, L., Long, S., Ke, X., Fukunaga, K., Lu, Y., & Han, F. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01081-0 · Cited by 295
Sex and gender in neurodevelopmental conditions
Bölte, S., Neufeld, J., Marschik, P. B., Williams, Z. J., Gallagher, L., & Lai, M.-C. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00774-6 · Cited by 249
Genomics, convergent neuroscience and progress in understanding autism spectrum disorder
Willsey, H. R., Willsey, A. J., Wang, B., & State, M. W. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00576-7 · Cited by 239
Metadata
- Authors
- Autism Sequencing Consortium, Doan, R. N., Lim, E. T., De Rubeis, S., Betancur, C., Cutler, D. J., Chiocchetti, A. G., Overman, L. M., Soucy, A., Goetze, S., Freitag, C. M., Daly, M. J., Walsh, C. A., Buxbaum, J. D., & Yu, T. W.
- Affiliations
- Boston Children's Hospital (US)
- Centre National de la Recherche Scientifique (FR)
- Emory University (US)
- Goethe University Frankfurt (DE)
- Centre for Life (GB)
- Broad Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Yu, Timothy W.
- ORCID
- Venue
- Nature Genetics
- Published
- 2019-06-17
- Volume
- 51
- Issue
- 7
- Pages
- 1092-1098
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6629034
- OpenAlex
- W2952501183
- Cited by
- 159
- References
- 60
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 27 · 2023: 21 · 2022: 31 · 2021: 26 · 2020: 27 · 2019: 3
- FWCI
- 12.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- HAL (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Wellcome Trust
- National Institutes of Health (5rc2mh089952-02, 1s10rr028832-01)
- Medical Research Council (MR/R006237/1)
- National Institute of Mental Health (U01MH100209, R01MH083565, U01MH111661, U01MH100229, R01MH113761, R01MH097849, U01MH111658, RC2-MH089952, U01MH100239, R56MH097849, U01MH111662, U01MH111660, U01MH100233)
- National Institute of Neurological Disorders and Stroke (T32NS007484)
- National Center for Research Resources (S10 RR028832)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U24HD093487, U19HD077671)
- 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 › Genomics and Rare Diseases
- Keywords
- autism spectrum disorder, recessive mutations, biallelic loss-of-function variants, neurodevelopmental genes, FEV, CA2, NSUN2, PAHs, retinoic acid receptor beta, SLC1A1, USH2A, rare variants
- MeSH terms
- Autism Spectrum Disorder, Exome Sequencing, Female, Genes, Recessive, Humans, Male, Cohort Studies, Genome, Human, Case-Control Studies, Genetic Predisposition to Disease, Mutation, Missense, Allelic Imbalance
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
