Abstract
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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Acknowledgements
We would like to thank the families, the patients, and clinical staff at all locations for participation in this study. We are very grateful to Dr Xinmin Li, Jonathan David, Vanina Tomasina, Traci Toy, and Lynn Yang for their technical assistance on CMA, CES, and FISH analysis, and the UCLA-CGC Genomic Data Board members for their contribution to exome data interpretation. We thank Drs Aviv Paz and Thorsten Althoff for their assistance in structure analysis and figure generation, Dr Sulagna Saitta for useful discussion, and Dr Kevin M Squire for his critical reading of this manuscript. This work was partially presented at the 2014 American College of Medical Genetics and Genomics annual meeting, 26–29 March, Nashville, TN, USA, and the 35th David Smith Workshop on Morphogenesis and Dysmorphology at University of Madison, WI, 25–30 July, 2014. This study was supported by NIH grant GM078844 (JA), and the UCLA Department of Pathology translational research fund (FQ-R).
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Ji, J., Lee, H., Argiropoulos, B. et al. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. Eur J Hum Genet 23, 1473–1481 (2015). https://doi.org/10.1038/ejhg.2015.71
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DOI: https://doi.org/10.1038/ejhg.2015.71
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