The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy
Abstract
Background: DYRK1A plays different functions during development, with an important role in controlling brain growth through neuronal proliferation and neurogenesis. It is expressed in a gene dosage dependent manner since dyrk1a haploinsufficiency induces a reduced brain size in mice, and DYRK1A overexpression is the candidate gene for intellectual disability (ID) and microcephaly in Down syndrome. We have identified a 69 kb deletion including the 5′ region of the DYRK1A gene in a patient with growth retardation, primary microcephaly, facial dysmorphism, seizures, ataxic gait, absent speech and ID. Because four patients previously reported with intragenic DYRK1A rearrangements or 21q22 microdeletions including only DYRK1A presented with overlapping phenotypes, we hypothesised that DYRK1A mutations could be responsible for syndromic ID with severe microcephaly and epilepsy. Methods: The DYRK1A gene was studied by direct sequencing and quantitative PCR in a cohort of 105 patients with ID and at least two symptoms from the Angelman syndrome spectrum (microcephaly < −2.5 SD, ataxic gait, seizures and speech delay). Results: We identified a de novo frameshift mutation (c.290_291delCT; p.Ser97Cysfs*98) in a patient with growth retardation, primary severe microcephaly, delayed language, ID, and seizures. Conclusion: The identification of a truncating mutation in a patient with ID, severe microcephaly, epilepsy, and growth retardation, combined with its dual function in regulating the neural proliferation/neuronal differentiation, adds DYRK1A to the list of genes responsible for such a phenotype. ID, microcephaly, epilepsy, and language delay are the more specific features associated with DYRK1A abnormalities. DYRK1A studies should be discussed in patients presenting such a phenotype.
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Mutations in DYRK1A and TCF4 cause syndromic diseases presenting with microcephaly and intellectual disability.
“Mutations in DYRK1A and TCF4 cause syndromic diseases presenting with microcephaly and intellectual disability97–105.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [102]
Among ASD genes affecting head size, CHD8 and PTEN mutations are associated with macrocephaly, while DYRK1A and CDKL5 mutations are associated with microcephaly.
“Among the ASD genes that have effects on head size, mutations in CHD8 (Bernier et al.) and PTEN (Butler et al., 2005) are associated with macrocephaly and mutations of DYRK1A (Courcet et al., 2012) and CDKL5 (Archer et al., 2006) are associated with microcephaly.”
From Getting to the cores of autism (2019) · cites this paper as Courcet et al., 2012
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Getting to the cores of autism
Iakoucheva, L. M., Muotri, A. R., & Sebat, J. (2019) · Cell · doi:10.1016/j.cell.2019.07.037 · Cited by 260 · see citing works
“Among the ASD genes that have effects on head size, mutations in CHD8 (Bernier et al., 2014) and PTEN (Butler et al., 2005) are associated withmacrocephaly, and mutations of DYRK1A (Courcet et al., 2012) and CDKL5 (Archer et al., 2006) are associated with microcephaly.”
BackgroundDisruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID
van Bon, B. W. M., Coe, B. P., Bernier, R., Green, C., Gerdts, J., Witherspoon, K., Kleefstra, T., Willemsen, M. H., Kumar, R., Bosco, P., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.5 · Cited by 204 · see citing works
Duchon, A., & Herault, Y. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00104 · Cited by 181 · see citing works
Soppa, U., Schumacher, J., Florencio Ortiz, V., Pasqualon, T., Tejedor, F., & Becker, W. (2014) · Cell Cycle · doi:10.4161/cc.29104 · Cited by 189 · see citing works
“A strong dosage effect of the human DYRK1A gene was further substantiated by the identification of patients with heterozygous loss-of-function mutations of the DYRK1A gene, who develop a severe syndrome of intellectual disability and microcephaly.(20,21) Importantly, impaired balance between proliferation and cell cyc…”
BackgroundJi, J., Lee, H., Argiropoulos, B., Dorrani, N., Mann, J., Martinez-Agosto, J. A., Gomez-Ospina, N., Gallant, N., Bernstein, J. A., Hudgins, L., et al. (2015) · European Journal of Human Genetics · doi:10.1038/ejhg.2015.71 · Cited by 145 · see citing works
Bronicki, L. M., Redin, C., Drunat, S., Piton, A., Lyons, M., Passemard, S., Baumann, C., Faivre, L., Thevenon, J., Rivière, J.-B., et al. (2015) · European Journal of Human Genetics · doi:10.1038/ejhg.2015.29 · Cited by 105 · see citing works
Self-citationNajas, S., Arranz, J., Lochhead, P. A., Ashford, A. L., Oxley, D., Delabar, J. M., Cook, S. J., Barallobre, M. J., & Arbonés, M. L. (2015) · EBioMedicine · doi:10.1016/j.ebiom.2015.01.010 · Cited by 92 · see citing works
Atas-Ozcan, H., Brault, V., Duchon, A., & Herault, Y. (2021) · Genes · doi:10.3390/genes12111833 · Cited by 78 · see citing works
Mozzi, A., Forni, D., Cagliani, R., Pozzoli, U., Clerici, M., & Sironi, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-06440-4 · Cited by 19 · see citing works
- Authors
- Courcet, J.-B., Faivre, L., Malzac, P., Masurel-Paulet, A., Lopez, E., Callier, P., Lambert, L., Lemesle, M., Thevenon, J., Gigot, N., Duplomb, L., Ragon, C., Marle, N., Mosca-Boidron, A.-L., Huet, F., Philippe, C., Moncla, A., & Thauvin-Robinet, C.
- Affiliations
- Université de Bourgogne (FR)
- Hôpital de la Timone (FR)
- Centre de Génétique et Centre de Référence Anomalies de Développement et Syndromes Malformatifs de l'interrégion Grand-Est, Hôpital d'Enfants, CHU, Dijon, France
- Service de médecine infantile III et de génétique clinique, Laboratoire de génétique, Unité de génétique du service néonatale, Maternité régionale de Nancy, Nancy, France
- CHU Dijon Bourgogne (FR)
- Equipe émergente GAD EA 4271 (Génétique des Anomalies du développement), IFR Santé STIC, Université de Bourgogne, Dijon, France
- Centre Hospitalier Régional et Universitaire de Nancy (FR)
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2012-10-25
- Volume
- 49
- Issue
- 12
- Pages
- 731-736
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- OpenAlex
- W2143060505
- Cited by
- 121
- References
- 32
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 10 · 2023: 15 · 2022: 12 · 2021: 9 · 2020: 6 · 2019: 10 · 2018: 10 · 2017: 9 · 2016: 7 · 2015: 10 · 2014: 10 · 2013: 3
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Conseil régional de Bourgogne-Franche-Comté
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- DYRK1A, syndromic intellectual disability, microcephaly, epilepsy, de novo frameshift mutation, truncating mutations, growth retardation, language delay, haploinsufficiency, neurodevelopmental disorders
- MeSH terms
- Dyrk Kinases, Adolescent, Base Sequence, Child, Child, Preschool, Electroencephalography, Epilepsy, Female, Genotype, Humans, Male, Intellectual Disability, Microcephaly, Mutation, Phenotype, Protein-Tyrosine Kinases, Syndrome, Protein Serine-Threonine Kinases, Facies, Gene Order
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