De Novo DYRK1A Point Mutations Cause Similar Phenotypes to Those Observed in Microdeletions including 21q22.13: Further Evidence for DYRK1As Critical Role in Brain Development. J. Ji1, N. Dorrani1, J. Mann2, J. A. Martinez-Agosto1, N. Gallant1, J. A. Bernstein3, N. Gomez-Ospina3, L. Hudgins3, L. Slattery3, B. Isidor4, E. Obersztyn5, B. Wiśniowiecka-Kowalnik5, M. Fox1, H. Lee1, J. Deignan1, E. Vilain1, S. F. Nelson1, W. Grody1, F. Quintero-Rivera1 1) University of California, Los Angeles (UCLA), Los Angeles, CA; 2) Kaiser Permanente, Fresno, CA; 3) Stanford University School of Medicine, Stanford, CA; 4) Centre Hospitalier Universitaire de Nantes, Paris, France; 5) Institute of Mother and Child, Warsaw, Poland.

   DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) is a highly conserved gene located in the Down syndrome critical region. It plays an important role in controlling brain growth through the regulation of neuronal proliferation and neurogenesis. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of DYRK1A disruption has not been fully explored. To characterize the landscape of DYRK1A disruptions and their associated phenotypes, we identified seven individuals ( from 17 months to 7 years old ) with de novo disruptions of DYRK1A; three with heterozygous microdeletions (1.7 to 4.2 Mb), and four with point mutations (2 missense and 2 nonsense). The genotype-phenotype analysis of all published cases and our cohort of patients (N=20), revealed that phenotypes were largely indistinguishable between patients with the 21q22.12q22.3 microdeletion and those with translocation or mutation limited to DYRK1A. All patients shared primary microcephaly (OFC <3%, -2SD), severe intellectual disability (ID), developmental delay (DD), severe speech impairment, and distinct facial features. Seizures, brain abnormalities, ataxia/abnormal gait, and feeding difficulties during infancy were present in two thirds of all patients. A less common feature was autism spectrum disorder (30%). The severity of the microcephaly varied from -2 SD to -6 SD. While Dyrk1a (-/-) is embryonic lethal, microcephaly and DD have been observed in Dyrk1a (+/-) deficient mouse models, and it has been demonstrated that Dyrk1a plays a vital role in shaping the brain, controlling cell density and cell morphology, and regulating developmental pathways. Although we cannot fully exclude contribution of other genes to the phenotypes in patients with a microdeletion, point mutations in DYRK1A are sufficient to recapitulate the neurodevelopmental abnormalities observed in the microdeletion cases. Our study further demonstrates that haploinsufficiency of DYRK1A results in primary microcephaly and ID in humans, and that genome-wide testing (e.g. exome sequencing, microarray) should be considered in patients with these phenotypes. Our report represents the largest cohort of patients with DYRK1A disruptions, and is the first attempt to achieve consistent genotype-phenotype correlations in the distinct group of subjects with 21q22.13 microdeletions and DYRK1A mutations.

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