Abstract
Whole exome sequencing (WES) has been utilized with increasing frequency to identify mutations underlying rare diseases. Autism spectrum disorders (ASD) and intellectual disability (ID) are genetically heterogeneous, and novel genes for these disorders are rapidly being identified, making these disorders ideal candidates for WES. Here we report a 17-year-old girl with ASD, developmental delay, ID, seizures, Chiari I malformation, macrocephaly, and short stature. She was found by WES to have a de novo c.2028delT (P677LfsX19) mutation in the SET domain-containing protein 2 (SETD2) gene, predicted to be gene-damaging. This case offers evidence for the potential the role of SETD2 in ASD and ID and provides further detail about the phenotypic manifestations of mutations in SETD2.
This is a preview of subscription content, log in via an institution to check access.
References
Adegbola, A., Gao, H., Sommer, S., & Browning, M. (2008). A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD). American Journal of Medical Genetics Part A, 146A(4), 505–511. doi:10.1002/ajmg.a.32142.
Bernier, R., Golzio, C., Xiong, B., Stessman, H. A., Coe, B. P., Penn, O., et al. (2014). Disruptive CHD8 mutations define a subtype of autism early in development. Cell, 158(2), 263–276. doi:10.1016/j.cell.2014.06.017.
Carrozza, M. J., Li, B., Florens, L., Suganuma, T., Swanson, S. K., Lee, K. K., et al. (2005). Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell, 123(4), 581–592. doi:10.1016/j.cell.2005.10.023.
Carvalho, S., Raposo, A. C., Martins, F. B., Grosso, A. R., Sridhara, S. C., Rino, J., et al. (2013). Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics during transcription. Nucleic Acids Research, 41(5), 2881–2893. doi:10.1093/nar/gks1472.
De Rubeis, S., He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Cicek, A. E., et al. (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 515(7526), 209–215. doi:10.1038/nature13772.
DePristo, M. A., Banks, E., Poplin, R., Garimella, K. V., Maguire, J. R., Hartl, C., et al. (2011). A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature Genetics, 43(5), 491–498. doi:10.1038/ng.806.
Fischbach, G. D., & Lord, C. (2010). The Simons Simplex Collection: A resource for identification of autism genetic risk factors. Neuron, 68(2), 192–195. doi:10.1016/j.neuron.2010.10.006.
Greer, E. L., & Shi, Y. (2012). Histone methylation: A dynamic mark in health, disease and inheritance. Nature Reviews Genetics, 13(5), 343–357. doi:10.1038/nrg3173.
Hoyer, J., Ekici, A. B., Endele, S., Popp, B., Zweier, C., Wiesener, A., et al. (2012). Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. American Journal of Human Genetics, 90(3), 565–572. doi:10.1016/j.ajhg.2012.02.007.
Iossifov, I., O’Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., et al. (2014). The contribution of de novo coding mutations to autism spectrum disorder. Nature, 515(7526), 216–221. doi:10.1038/nature13908.
Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., et al. (2012). De novo gene disruptions in children on the autistic spectrum. Neuron, 74(2), 285–299. doi:10.1016/j.neuron.2012.04.009.
Keogh, M. C., Kurdistani, S. K., Morris, S. A., Ahn, S. H., Podolny, V., Collins, S. R., et al. (2005). Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell, 123(4), 593–605. doi:10.1016/j.cell.2005.10.025.
Lasalle, J. M. (2013). Autism genes keep turning up chromatin. OA Autism, 1(2), 14.
Li, H., & Durbin, R. (2009). Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics, 25(14), 1754–1760. doi:10.1093/bioinformatics/btp324.
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., et al. (2009). The sequence alignment/map format and SAMtools. Bioinformatics, 25(16), 2078–2079. doi:10.1093/bioinformatics/btp352.
Luco, R. F., Pan, Q., Tominaga, K., Blencowe, B. J., Pereira-Smith, O. M., & Misteli, T. (2010). Regulation of alternative splicing by histone modifications. Science, 327(5968), 996–1000. doi:10.1126/science.1184208.
Luscan, A., Laurendeau, I., Malan, V., Francannet, C., Odent, S., Giuliano, F., et al. (2014). Mutations in SETD2 cause a novel overgrowth condition. Journal of Medical Genetics. doi:10.1136/jmedgenet-2014-102402.
Neale, B. M., Kou, Y., Liu, L., Ma’ayan, A., Samocha, K. E., Sabo, A., et al. (2012). Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature, 485(7397), 242–245. doi:10.1038/nature11011.
O’Roak, B. J., Deriziotis, P., Lee, C., Vives, L., Schwartz, J. J., Girirajan, S., et al. (2011). Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genetics, 43(6), 585–589. doi:10.1038/ng.835.
O’Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., et al. (2012a). Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science, 338(6114), 1619–1622. doi:10.1126/science.1227764.
O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., et al. (2012b). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 485(7397), 246–250. doi:10.1038/nature10989.
Pinto, D., Pagnamenta, A. T., Klei, L., Anney, R., Merico, D., Regan, R., et al. (2010). Functional impact of global rare copy number variation in autism spectrum disorders. Nature, 466(7304), 368–372. doi:10.1038/nature09146.
Ronan, J. L., Wu, W., & Crabtree, G. R. (2013). From neural development to cognition: Unexpected roles for chromatin. Nature Reviews Genetics, 14(5), 347–359. doi:10.1038/nrg3413.
Sanders, S. J., Ercan-Sencicek, A. G., Hus, V., Luo, R., Murtha, M. T., Moreno-De-Luca, D., et al. (2011). Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron, 70(5), 863–885. doi:10.1016/j.neuron.2011.05.002.
Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., et al. (2012). De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature, 485(7397), 237–241. doi:10.1038/nature10945.
Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., et al. (2007). Strong association of de novo copy number mutations with autism. Science, 316(5823), 445–449. doi:10.1126/science.1138659.
Shen, E., Shulha, H., Weng, Z., & Akbarian, S. (2014). Regulation of histone H3K4 methylation in brain development and disease. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. doi:10.1098/rstb.2013.0514.
Szatmari, P., Paterson, A. D., Zwaigenbaum, L., Roberts, W., Brian, J., Liu, X. Q., et al. (2007). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics, 39(3), 319–328. doi:10.1038/ng1985.
Acknowledgments
We thank the patient and her family for their contribution. This work was supported in part by NIH Grant 5 T35 DK 93430-2.
Conflict of interest
No potential conflict of interest was disclosed.
Informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for whom identifying information is included in this article.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lumish, H.S., Wynn, J., Devinsky, O. et al. Brief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy. J Autism Dev Disord 45, 3764–3770 (2015). https://doi.org/10.1007/s10803-015-2484-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10803-015-2484-8