Mutations in HECW2 are associated with intellectual disability and epilepsy
Open accessAbstract
Background: De novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions. Methods: Exome sequencing was performed on 39 patient–parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders. Results: In 39 patient–parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy. Conclusions: Our results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders.
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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 [19]
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Cites
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
dbSNP: the NCBI database of genetic variation
Sherry, S. T. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.1.308 · Cited by 7,502 · see citing works
A general framework for estimating the relative pathogenicity of human genetic variants
Kircher, M., Witten, D. M., Jain, P., O'Roak, B. J., Cooper, G. M., & Shendure, J. (2014) · Nature Genetics · doi:10.1038/ng.2892 · Cited by 6,183 · see citing works
Warde-Farley, D., Donaldson, S. L., Comes, O., Zuberi, K., Badrawi, R., Chao, P., Franz, M., Grouios, C., Kazi, F., Lopes, C. T., et al. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq537 · Cited by 4,835 · see citing works
Miller, D. T., Adam, M. P., Aradhya, S., Biesecker, L. G., Brothman, A. R., Carter, N. P., Church, D. M., Crolla, J. A., Eichler, E. E., Epstein, C. J., et al. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.04.006 · Cited by 2,882 · see citing works
Self-citationSynaptic, 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 · see citing works
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
De 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 · 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
De novo mutations in epileptic encephalopathies
Epi4K Consortium, & Epilepsy Phenome/Genome Project (2013) · Nature · doi:10.1038/nature12439 · Cited by 1,514 · see citing works
Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing
Yang, Y., Muzny, D. M., Xia, F., Niu, Z., Person, R., Ding, Y., Ward, P., Braxton, A., Wang, M., Buhay, C., et al. (2014) · JAMA · doi:10.1001/jama.2014.14601 · Cited by 1,360 · 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
Large-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
Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing
Roach, J. C., Glusman, G., Smit, A. F. A., Huff, C. D., Hubley, R., Shannon, P. T., Rowen, L., Pant, K. P., Goodman, N., Bamshad, M., et al. (2010) · Science · doi:10.1126/science.1186802 · Cited by 1,084 · see citing works
Rauch, A., Wieczorek, D., Graf, E., Wieland, T., Endele, S., Schwarzmayr, T., Albrecht, B., Bartholdi, D., Beygo, J., Di Donato, N., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61480-9 · Cited by 1,041 · 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
Richards, C. S., Bale, S., Bellissimo, D. B., Das, S., Grody, W. W., Hegde, M. R., Lyon, E., & Ward, B. E. (2008) · Genetics in Medicine · doi:10.1097/gim.0b013e31816b5cae · Cited by 832 · see citing works
Wright, C. F., Fitzgerald, T. W., Jones, W. D., Clayton, S., McRae, J. F., van Kogelenberg, M., King, D. A., Ambridge, K., Barrett, D. M., Bayzetinova, T., et al. (2014) · The Lancet · doi:10.1016/s0140-6736(14)61705-0 · Cited by 728 · see citing works
Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1
Carvill, G. L., Heavin, S. B., Yendle, S. C., McMahon, J. M., O'Roak, B. J., Cook, J., Khan, A., Dorschner, M. O., Weaver, M., Calvert, S., et al. (2013) · Nature Genetics · doi:10.1038/ng.2646 · Cited by 687 · see citing works
Francioli, L. C., Menelaou, A., Pulit, S. L., Elbers, C. C., Kloosterman, W. P., van Setten, J., Nijman, I. J., Renkens, I., de Bakker, P. I. W., van Dijk, F., et al. (2014) · Nature Genetics · doi:10.1038/ng.3021 · Cited by 642 · see citing works
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 · see citing works
Horizontal spread of synchronized activity in neocortex and its control by GABA-mediated inhibition
Amitai, Y., & Connors, B. W. (1989) · Journal of Neurophysiology · doi:10.1152/jn.1989.61.4.747 · Cited by 535 · see citing works
Jiang, Y.-H., Yuen, R. K. C., Jin, X., Wang, M., Chen, N., Wu, X., Ju, J., Mei, J., Shi, Y., He, M., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.06.012 · Cited by 474 · see citing works
Hagman, K. D. F., Shahmirzadi, L., El‐Khechen, D., Powis, Z., Chao, E., Davis, B. T., Baxter, R. M., Zeng, W., Mroske, C., Parra, M. C., et al. (2014) · Genetics in Medicine · doi:10.1038/gim.2014.154 · Cited by 469 · see citing works
Exome sequencing supports a de novo mutational paradigm for schizophrenia
Xu, B., Roos, J. L., Dexheimer, P. J., Boone, B. E., Plummer, B., Levy, S., Gogos, J. A., & Karayiorgou, M. (2011) · Nature Genetics · doi:10.1038/ng.902 · Cited by 461 · see citing works
De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
Appenzeller, S., Balling, R., Barisic, N., Baulac, S., Caglayan, H., Craiu, D., De Jonghe, P., Depienne, C., Dimova, P., Djémié, T., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.08.013 · Cited by 439 · see citing works
Tammimies, K., Marshall, C. R., Walker, S., Kaur, G., Thiruvahindrapuram, B., Lionel, A. C., Yuen, R. K. C., Uddin, M., Roberts, W., Weksberg, R., et al. (2015) · JAMA · doi:10.1001/jama.2015.10078 · Cited by 419 · see citing works
Helbig, K. L., Hagman, K. D. F., Shinde, D. N., Mroske, C., Powis, Z., Li, S., Tang, S., & Helbig, I. (2016) · Genetics in Medicine · doi:10.1038/gim.2015.186 · Cited by 368 · see citing works
Genetics of Early Onset Cognitive Impairment
Ropers, H. (2010) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-082509-141640 · Cited by 365 · see citing works
The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping
Brown, S. D. M., & Moore, M. W. (2012) · Mammalian Genome · doi:10.1007/s00335-012-9427-x · Cited by 282 · see citing works
Epilepsy in adults with intellectual disabilities: Prevalence, associations and service implications
McGrother, C. W., Bhaumik, S., Thorp, C. F., Hauck, A., Branford, D. M. L., & Watson, J. M. (2006) · Seizure · doi:10.1016/j.seizure.2006.04.002 · Cited by 241 · see citing works
WSTF–ISWI chromatin remodeling complex targets heterochromatic replication foci
Bozhenok, L., Wade, P. A., & Varga‐Weisz, P. (2002) · The EMBO Journal · doi:10.1093/emboj/21.9.2231 · Cited by 236 · see citing works
Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation
Kato, M., Yamagata, T., Kubota, M., Arai, H., Yamashita, S., Nakagawa, T., Fujii, T., Sugai, K., Imai, K., Uster, T., et al. (2013) · Epilepsia · doi:10.1111/epi.12200 · Cited by 226 · see citing works
CPD — Education and self-assessment The epidemiology of epilepsy: the size of the problem
Bell, G. S., & Sander, J. W. A. S. (2001) · Seizure · doi:10.1053/seiz.2001.0584 · Cited by 214 · see citing works
Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios
Besenbacher, S., Liu, S. M., Izarzugaza, J. M. G., Grove, J., Belling, K., Bork‐Jensen, J., Huang, S., Als, T. D., Li, S., Yadav, R., et al. (2015) · Nature Communications · doi:10.1038/ncomms6969 · Cited by 173 · see citing works
Liao, Y., Anttonen, A.-K., Liukkonen, E., Gaily, E., Maljevic, S., Schubert, S., Bellan-Koch, A., Petrou, S., Ahonen, V. E., Lerche, H., et al. (2010) · Neurology · doi:10.1212/wnl.0b013e3181f8812e · Cited by 170 · see citing works
FLAGS, frequently mutated genes in public exomes
Shyr, C., Tarailo‐Graovac, M., Gottlieb, M., Lee, J. J. Y., van Karnebeek, C., & Wasserman, W. W. (2014) · BMC Medical Genomics · doi:10.1186/s12920-014-0064-y · Cited by 169 · see citing works
Grozeva, D., Carss, K., Spasić-Bošković, O., Parker, M. J., Archer, H. L., Firth, H. V., Park, S., Canham, N. L. E., Holder, S., Wilson, M., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.03.006 · Cited by 164 · see citing works
The Epidemiology of Epilepsy and Learning Disability
Lhatoo, S. D., & Sander, J. W. A. S. (2001) · Epilepsia · doi:10.1046/j.1528-1157.2001.00502.x · Cited by 153 · see citing works
ELKS2α/CAST deletion selectively increases neurotransmitter release at inhibitory synapses
Kaeser, P. S., Deng, L., Chávez, A. E., Liu, X., Castillo, P. E., & Südhof, T. C. (2009) · Neuron · doi:10.1016/j.neuron.2009.09.019 · Cited by 102 · see citing works
DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior
Ioannou, M. S., Bell, E. S., Girard, M., Chaineau, M., Hamlin, J. N. R., Daubaras, M., Monast, A., Park, M., Hodgson, L., & McPherson, P. S. (2015) · The Journal of Cell Biology · doi:10.1083/jcb.201407068 · Cited by 88 · see citing works
Lu, L., Hu, S., Wei, R., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.472076 · Cited by 47 · see citing works
Rademacher, N., Hambrock, M., Fischer, U., et al. (2011) · Neurogenetics · doi:10.1007/s10048-011-0277-6 · Cited by 36 · see citing works
Disruption of ST5 is associated with mental retardation and multiple congenital anomalies
Göhring, I., Tagariello, A., Endele, S. U., et al. (2009) · Journal of Medical Genetics · doi:10.1136/jmg.2009.069799 · Cited by 17 · see citing works
Winawer, M. R., Klassen, T., Teed, S., Shipman, M., Leung, E., & Palmer, A. A. (2013) · Genes Brain & Behavior · doi:10.1111/gbb.12116 · Cited by 5 · see citing works
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- [2]Bell GS, Sander JW The epidemiology of epilepsy: the size of the problem. Seizure 2002; 11 (Suppl A): 306– 14; quiz 315–16. 12185766
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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
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
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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
Deliu, E., Arecco, N., Morandell, J., Dotter, C. P., Contreras, X., Girardot, C., Käsper, E.-L., Kozlova, A., Kishi, K., Chiaradia, I., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0266-2 · Cited by 89 · 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
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Vevera, J., Zarrei, M., Hartmannová, H., Jedličková, I., Mušálková, D., Přistoupilová, A., Oliveriusová, P., Trešlová, H., Nosková, L., Hodaňová, K., et al. (2019) · Genes, Brain and Behavior · doi:10.1111/gbb.12536 · Cited by 15 · see citing works
- Authors
- Halvardson, J., Zhao, J. J., Zaghlool, A., Wentzel, C., Georgii-Hemming, P., Månsson, E., Ederth Sävmarker, H., Brandberg, G., Soussi Zander, C., Thuresson, A.-C., & Feuk, L.
- Affiliations
- Uppsala University (SE)
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden
- Örebro University Hospital (SE)
- Department of Pediatrics, Gävle Hospital, Gävle, Sweden
- Pediatric Clinic, Falun, Sweden
- Corresponding author
- Feuk, Lars
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2016-06-22
- Volume
- 53
- Issue
- 10
- Pages
- 697-704
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- PMC
- PMC5099177
- OpenAlex
- W2465916929
- Cited by
- 71
- References
- 46
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 2 · 2023: 2 · 2022: 14 · 2021: 10 · 2020: 8 · 2019: 6 · 2018: 8 · 2017: 7
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of Medical Genetics (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Norges Forskningsråd
- Science for Life Laboratory
- Medical Research Council
- Uppsala Multidisciplinary Center for Advanced Computational Science
- National Institute of General Medical Sciences (R01GM097376)
- FP7 Ideas: European Research Council (282330)
- 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 › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- HECW2, intellectual disability, epilepsy, de novo mutations, neurodevelopmental disorders, candidate genes, molecular diagnosis, exome sequencing, network analysis, variants of uncertain significance
- MeSH terms
- DNA Mutational Analysis, Epilepsy, Female, Humans, Male, Intellectual Disability, Mutation, Syndrome, Ubiquitin-Protein Ligases, Exome
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