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Eur J Hum Genet. 2015 Nov;23(11):1473-81. doi: 10.1038/ejhg.2015.71. Epub 2015 May 6.

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.

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Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
UCLA Clinical Genomics Center, Los Angeles, CA, USA.
Department of Medical Genetics, Cumming School of Medicine, University of Calgary, and Alberta Children's Hospital Research Institute for Child and Maternal Health, Calgary, AB, Canada.
Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
Kaiser Permanente, Fresno, CA, USA.
Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
CHU Nantes, Service de Génétique Médicale, and Inserm UMR957, Faculté de Médecine, Nantes, France.
Institute of Mother and Child, Warsaw, Poland.
Seattle Children's Research Institute, Seattle, WA, USA.
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Radiology, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
Department of Physiology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
The Institute for Stem Cell Biology and Regenerative Medicine (inStem), National Centre for Biological Sciences-Tata Institute of Fundamental Research, Bangalore, Karnataka, India.


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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