DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies
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Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.
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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 [101]
For both DYRK1A and TCF4, haploinsufficiency is often associated with disease, indicating that adequate expression levels of these proteins are essential for neurodevelopment.
“For both genes haploinsufficiency is often associated with disease, indicating that adequate expression levels of these proteins are essential for neurodevelopment98, 101, 106.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [101]
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- Authors
- Ji, J., Lee, H., Argiropoulos, B., Dorrani, N., Mann, J., Martinez-Agosto, J. A., Gomez-Ospina, N., Gallant, N., Bernstein, J. A., Hudgins, L., Slattery, L., Isidor, B., Le Caignec, C., David, A., Obersztyn, E., Wiśniowiecka-Kowalnik, B., Fox, M., Deignan, J. L., Vilain, E., Hendricks, E., Horton Harr, M., Noon, S. E., Jackson, J. R., Wilkens, A., Mirzaa, G., Salamon, N., Abramson, J., Zackai, E. H., Krantz, I., Innes, A. M., Nelson, S. F., Grody, W. W., & Quintero-Rivera, F.
- Affiliations
- University of California, Los Angeles (US)
- University of Calgary (CA)
- Kaiser Permanente (US)
- Stanford Medicine (US)
- Inserm (FR)
- Instytut Matki i Dziecka (PL)
- Seattle Children's Research Institute (US)
- Children's Hospital of Philadelphia (US)
- Tata Institute of Fundamental Research (IN)
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2015-05-06
- Volume
- 23
- Issue
- 11
- Pages
- 1473-1481
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- PMC
- PMC4613469
- OpenAlex
- W1520236834
- Cited by
- 145
- References
- 46
- Citations by year
- 2026: 14 · 2025: 8 · 2024: 20 · 2023: 19 · 2022: 12 · 2021: 25 · 2020: 10 · 2019: 8 · 2018: 8 · 2017: 13 · 2016: 7 · 2015: 1
- FWCI
- 6.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (GM078844, R01GM078844)
- National Institute of Neurological Disorders and Stroke (K08NS092898)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- 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
- DYRK1A, haploinsufficiency, Down syndrome critical region, microcephaly, intellectual disability, speech disorders, facial dysmorphism, genotype-phenotype correlation, de novo mutations, seizures, developmental delay, short stature
- MeSH terms
- Abnormalities, Multiple, Dyrk Kinases, Chromosome Deletion, Down Syndrome, Female, Humans, Male, Intellectual Disability, Microcephaly, Phenotype, Protein-Tyrosine Kinases, Protein Serine-Threonine Kinases, Facies, Polymorphism, Single Nucleotide, Haploinsufficiency
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