Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability
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Abstract
To identify candidate genes for intellectual disability, we performed a meta-analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient-parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4, PPM1D, RAC1, SMAD6, SON, SOX5, SYNCRIP, TCF20, TLK2 and TRIP12. In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes.
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The prevalence of ASD in several ID/DD-ascertained cohorts is not quantified, and the prevalence of ID in ASD-ascertained cohorts is known only for a minority subset of participants.
“Because of this bias, the phenotypic overlap between the groups is unclear; the prevalence of ASD in several of the ID/DD-ascertained cohorts is not quantified,13, 14, 15,18,19 and the prevalence of ID in the ASD-ascertained cohorts is known only for a minority subset of participants.11,12”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [15]
The ID/DD cohorts evaluated in the Satterstrom and Coe studies overlapped almost completely; each study used samples from five previously published studies, and four of the five were the same studies, accounting for 99% of the samples.
“In fact, the ID/DD cohorts evaluated in these two studies overlapped almost completely; each study used samples from five previously published studies, and four of the five were the same studies, accounting for 99% of the samples.11, 12, 13, 14, 15, 16”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [15]
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Cites
The contribution of de novo coding mutations to autism spectrum disorder
Iossifov, I., O’Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Witherspoon, K. T., Vives, L., Patterson, K. E., et al. (2014) · Nature · doi:10.1038/nature13908 · Cited by 2,585 · see citing works
Rate of de novo mutations and the importance of father’s age to disease risk
Kong, A., Frigge, M. L., Masson, G., Besenbacher, S., Sulem, P., Magnusson, G., Gudjonsson, S. A., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., et al. (2012) · Nature · doi:10.1038/nature11396 · Cited by 2,134 · see citing works
Patterns and rates of exonic de novo mutations in autism spectrum disorders
Neale, B. M., Kou, Y., Liu, L., Ma’ayan, A., Samocha, K. E., Sabo, A., Lin, C.-F., Stevens, C., Wang, L.-S., Makarov, V., et al. (2012) · Nature · doi:10.1038/nature11011 · Cited by 1,734 · see citing works
Diagnostic exome sequencing in persons with severe intellectual disability
de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1206524 · Cited by 1,546 · see citing works
Self-citationA Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes
MacArthur, D. G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J. K., Montgomery, S. B., et al. (2012) · Science · doi:10.1126/science.1215040 · Cited by 1,272 · see citing works
Genome sequencing identifies major causes of severe intellectual disability
Gilissen, C., Hehir-Kwa, J. Y., Thung, D. T., van de Vorst, M., van Bon, B. W. M., Willemsen, M. H., Kwint, M., Janssen, I. M., Hoischen, A., Schenck, A., et al. (2014) · Nature · doi:10.1038/nature13394 · Cited by 1,125 · see citing works
Self-citationLarge-scale discovery of novel genetic causes of developmental disorders
Study, T. D. D. D. (2015) · Nature · doi:10.1038/nature14135 · Cited by 1,124 · see citing works
A framework for the interpretation of de novo mutation in human disease
Samocha, K. E., Robinson, E. B., Sanders, S. J., Stevens, C., Sabo, A., McGrath, L. M., Kosmicki, J. A., Rehnström, K., Mallick, S., Kirby, A., et al. (2014) · Nature Genetics · doi:10.1038/ng.3050 · Cited by 979 · see citing works
Genic Intolerance to Functional Variation and the Interpretation of Personal Genomes
Petrovski, S., Wang, Q., Heinzen, E. L., Allen, A. S., & Goldstein, D. B. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003709 · Cited by 901 · see citing works
Gulsuner, S., Walsh, T., Watts, A. C., Lee, M. K., Thornton, A. M., Casadei, S., Rippey, C., Shahin, H., Braff, D., Cadenhead, K. S., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.049 · Cited by 536 · see citing works
De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia
Xu, B., Ionita-Laza, I., Roos, J. L., Boone, B., Woodrick, S., Sun, Y., Levy, S., Gogos, J. A., & Karayiorgou, M. (2012) · Nature Genetics · doi:10.1038/ng.2446 · Cited by 442 · see citing works
A de novo convergence of autism genetics and molecular neuroscience
Krumm, N., O’Roak, B. J., Shendure, J., & Eichler, E. E. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2013.11.005 · Cited by 423 · see citing works
Multiple hypothesis testing in genomics
Goeman, J., & Solari, A. (2014) · Statistics in Medicine · doi:10.1002/sim.6082 · Cited by 377 · see citing works
Recurrent de novo mutations implicate novel genes underlying simplex autism risk
O'Roak, B. J., Stessman, H. A., Boyle, E. A., Witherspoon, K. T., Martin, B., Lee, C., Vives, L., Baker, C., Hiatt, J. B., Nickerson, D. A., et al. (2014) · Nature Communications · doi:10.1038/ncomms6595 · Cited by 336 · see citing works
Neveling, K., Feenstra, I., Gilissen, C., Hoefsloot, L. H., Kamsteeg, E., Mensenkamp, A. R., Rodenburg, R. J., Yntema, H. G., Spruijt, L., Vermeer, S., et al. (2013) · Human Mutation · doi:10.1002/humu.22450 · Cited by 331 · see citing works
Self-citationMutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures
Carvill, G. L., McMahon, J. M., Schneider, A., Zemel, M., Myers, C. T., Saykally, J., Nguyen, J., Robbiano, A., Zara, F., Specchio, N., et al. (2015) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.02.016 · Cited by 227 · see citing works
How many human genes can be defined as housekeeping with current expression data?
Zhu, J., He, F., Song, S., Wang, J., & Yu, J. M. (2008) · BMC Genomics · doi:10.1186/1471-2164-9-172 · Cited by 149 · see citing works
Analysis of protein-coding genetic variation in 60,706 humansPreprint
Lek, M., Karczewski, K. J., Minikel, E. V., et al. (2015) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/030338 · Cited by 144 · see citing works
Mutations in SETD2 cause a novel overgrowth condition
Luscan, A., Laurendeau, I., Malan, V., Francannet, C., Odent, S., Giuliano, F., Lacombe, D., Touraine, R. L., Vidaud, M., Pasmant, É., et al. (2014) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2014-102402 · Cited by 133 · see citing works
Strom, S. P., Lee, H., Das, K., Vilain, E. J. N., Nelson, S. F., Grody, W. W., & Deignan, J. L. (2014) · Genetics in Medicine · doi:10.1038/gim.2013.183 · Cited by 131 · see citing works
Brief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy
Lumish, H. S., Wynn, J., Devinsky, O., & Chung, W. K. (2015) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-015-2484-8 · Cited by 81 · see citing works
Deciphering Developmental Disorders
Wright, C. F., Firth, H. V., Fitzpatrick, D. L., et al. (2012) · Journal of Medical Genetics · Cited by 53 · see citing works
McRae, J. F., Clayton, S., Fitzgerald, T. W., Kaplanis, J., Prigmore, E., Rajan, D., Sifrim, A., Aitken, S., Akawi, N., Alvi, M., et al. (2016) · doi:10.1101/049056 · Cited by 30 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- O'Roak, B.J. et al. Nat. Commun. 5, 5595 (2014).
- Zhu, J., He, F., Song, S., Wang, J. & Yu, J. BMC Genomics 9, 172 (2008).
- Petrovski, S., Wang, Q., Heinzen, E.L., Allen, A.S. & Goldstein, D.B. PLoS Genet. 9, e1003709 (2013).
Cited by
Sorted by citations
Prevalence and architecture of de novo mutations in developmental disorders
Study, D. D. D. (2017) · Nature · doi:10.1038/nature21062 · Cited by 1,480 · see citing works
Presence of Genetic Variants Among Young Men With Severe COVID-19
van der Made, C. I., Simons, A., Schuurs-Hoeijmakers, J., van den Heuvel, G., Mantere, T., Kersten, S., van Deuren, R. C., Steehouwer, M., van Reijmersdal, S. V., Jaeger, M., et al. (2020) · JAMA · doi:10.1001/jama.2020.13719 · Cited by 789 · see citing works
Self-citationDendritic structural plasticity and neuropsychiatric disease
Forrest, M. P., Parnell, E., & Penzes, P. (2018) · Nature Reviews Neuroscience · doi:10.1038/nrn.2018.16 · Cited by 464 · see citing works
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies
Hamdan, F. F., Myers, C. T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A. D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.09.008 · Cited by 445 · see citing works
Self-citationRegional missense constraint improves variant deleteriousness prediction
Samocha, K. E., Kosmicki, J. A., Karczewski, K. J., O’Donnell-Luria, A. H., Pierce-Hoffman, E., MacArthur, D. G., Neale, B. M., & Daly, M. J. (2017) · doi:10.1101/148353 · Cited by 351 · see citing works
Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity
Coe, B. P., Stessman, H. A. F., Sulovari, A., Geisheker, M. R., Bakken, T. E., Lake, A. M., Dougherty, J. D., Lein, E. S., Hormozdiari, F., Bernier, R. A., et al. (2019) · Nature Genetics · doi:10.1038/s41588-018-0288-4 · Cited by 330 · see citing works
Kosmicki, J. A., Samocha, K. E., Howrigan, D. P., Sanders, S. J., Slowikowski, K., Lek, M., Karczewski, K. J., Cutler, D. J., Devlin, B., Roeder, K., et al. (2017) · Nature Genetics · doi:10.1038/ng.3789 · Cited by 340 · see citing works
Acuna-Hidalgo, R., Sengul, H., Steehouwer, M., van de Vorst, M., Vermeulen, S. H., Kiemeney, L. A. L. M., Veltman, J. A., Gilissen, C., & Hoischen, A. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.05.013 · Cited by 264 · see citing works
Self-citationHowrigan, D. P., Rose, S. A., Samocha, K. E., Fromer, M., Cerrato, F., Chen, W. J., Churchhouse, C., Chambert, K., Chandler, S. D., Daly, M. J., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0564-3 · Cited by 168 · see citing works
Insufficient Evidence for “Autism-Specific” Genes
Myers, S. M., Challman, T. D., Bernier, R., Bourgeron, T., Chung, W. K., Constantino, J. N., Eichler, E. E., Jacquemont, S., Miller, D. T., Mitchell, K. J., et al. (2020) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2020.04.004 · Cited by 165 · see citing works
Gabriele, M., Vulto-van Silfhout, A. T., Germain, P.-L., Vitriolo, A., Kumar, R., Douglas, E., Haan, E., Kosaki, K., Takenouchi, T., Rauch, A., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.05.006 · Cited by 163 · see citing works
Smith, R. S., Kenny, C. J., Ganesh, V., Jang, A., Borges-Monroy, R., Partlow, J. N., Hill, R. S., Shin, T., Chen, A. Y., Doan, R. N., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.07.052 · Cited by 160 · see citing works
Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications
Wilfert, A. B., Sulovari, A., Turner, T. N., Coe, B. P., & Eichler, E. E. (2017) · Genome Medicine · doi:10.1186/s13073-017-0498-x · Cited by 144 · see citing works
De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism
Hiraide, T., Nakashima, M., Yamoto, K., Fukuda, T., Kato, M., Ikeda, H., Sugie, Y., Aoto, K., Kaname, T., Nakabayashi, K., et al. (2018) · Human Genetics · doi:10.1007/s00439-017-1863-y · Cited by 75 · see citing works
Wang, W., Corominas, R., & Lin, G. N. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00258 · Cited by 70 · see citing works
Reijnders, M. R. F., Kousi, M., van Woerden, G. M., Klein, M., Bralten, J., Mancini, G. M. S., van Essen, T., Proietti-Onori, M., Smeets, E. E. J., van Gastel, M., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00933-6 · Cited by 76 · see citing works
The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia
Nehme, R., Pietiläinen, O., Artomov, M., Tegtmeyer, M., Valakh, V., Lehtonen, L., Bell, C., Singh, T., Trehan, A., Sherwood, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31436-8 · Cited by 58 · see citing works
Khazeeva, G., Sablauskas, K., van der Sanden, B., Steyaert, W., Kwint, M., Rots, D., Hinne, M., van Gerven, M., Yntema, H., Vissers, L., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac511 · Cited by 30 · see citing works
Self-citationDeleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder
Hiatt, S. M., Thompson, M. L., Prokop, J. W., Lawlor, J. M. J., Gray, D. E., Bebin, E. M., Rinne, T., Kempers, M., Pfundt, R., van Bon, B. W., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.02.002 · Cited by 29 · see citing works
Self-citationFamily-based genome-wide association study of autism spectrum disorder in middle eastern families
Al-Sarraj, Y., Al-Dous, E., Taha, R. Z., Ahram, D., Alshaban, F., Tolfat, M., El-Shanti, H., & Albagha, O. M. E. (2021) · Genes · doi:10.3390/genes12050761 · Cited by 17 · see citing works
Satterstrom, F. K., Kosmicki, J. A., Wang, J., Breen, M. S., De Rubeis, S., An, J.-Y., Peng, M., Collins, R., Grove, J., Klei, L., et al. (2018) · doi:10.1101/484113 · Cited by 2,323 · see citing works
“Unsurprisingly, many ASD 14 genes are also associated with NDD (22-26).”
Background
- Authors
- Lelieveld, S. H., Reijnders, M. R. F., Pfundt, R., Yntema, H. G., Kamsteeg, E.-J., de Vries, P., de Vries, B. B. A., Willemsen, M. H., Kleefstra, T., Löhner, K., Vreeburg, M., Stevens, S. J. C., van der Burgt, I., Bongers, E. M. H. F., Stegmann, A. P. A., Rump, P., Rinne, T., Nelen, M. R., Veltman, J. A., Vissers, L. E. L. M., Brunner, H. G., & Gilissen, C.
- Affiliations
- Radboud University Medical Center (NL)
- University Medical Center Groningen (NL)
- Maastricht University Medical Centre (NL)
- Corresponding author
- Gilissen, Christian
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2016-08-01
- Volume
- 19
- Issue
- 9
- Pages
- 1194-1196
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2506784803
- Cited by
- 442
- References
- 23
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 41 · 2023: 46 · 2022: 46 · 2021: 51 · 2020: 58 · 2019: 59 · 2018: 57 · 2017: 38 · 2016: 10
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Research Publications (Maastricht University) (acceptedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Keywords
- intellectual disability, de novo mutations, novel candidate genes, exome sequencing, clinical phenotype, PSD-95, PPM1D, Rac1, Smad6, sons, SOX5, SYNCRIP, TLK2, TRIP12
- MeSH terms
- Protein Phosphatase 2C, Disks Large Homolog 4 Protein, Carrier Proteins, DNA-Binding Proteins, Humans, Membrane Proteins, Intellectual Disability, Mutation, Phenotype, Protein Kinases, Transcription Factors, Minor Histocompatibility Antigens, rac1 GTP-Binding Protein, Heterogeneous-Nuclear Ribonucleoproteins, Ubiquitin-Protein Ligases, Intracellular Signaling Peptides and Proteins, Smad6 Protein, SOXD Transcription Factors, Exome
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