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

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/broadbased 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.

Cellular Phenotypes in Human iPSC-Derived Neurons from a Genetic Model of Autism Spectrum Disorder

“…Interestingly, the targeted deletion of one allele of the kinase Dyrk1a in mice resulted in decreased brain volume, and the authors observed reduced neuronal size and dendritic complexity, similar to our observations in 16pdup neurons(Benavides-Piccione et al, 2005; Fotaki et al, 2002). This kinase is involved in regulation of the PI3K/AKT and Ras/MAPK pathways and hence it is likely that its disruption may result in aberrant neuronal differentiation via dysregulation of these pathways(Ji et al, 2015). However, in humans, microcephaly has not previously been linked with somatic growth defects(Gilmore and Walsh, 2013).…”

“…Other CNVs such as the 1q21.1 duplication predispose to ASD and macrocephaly in addition to intellectual disability (ID) and schizophrenia (Mefford et al, 2008; Milone et al, 2016). In contrast, microcephaly is observed in carriers with mutations in DYRK1A along with predisposition for ID, ASD and seizures (Ji et al, 2015). Although both macrocephaly and microcephaly can be associated with ASD, studies demonstrating that the same gene (or pathway) can cause both macrocephaly and microcephaly (e.g.…”

Combined Treatment With Environmental Enrichment and (-)-Epigallocatechin-3-Gallate Ameliorates Learning Deficits and Hippocampal Alterations in a Mouse Model of Down Syndrome

“…In the hippocampus, Dyrk1A heterozygous mice show a significant reduction in hippocampal thickness, accompanied by decreases in cell number in CA1, CA2, CA3, and DG (Arqué et al, 2008). Humans with de novo heterozygous variants of DYRK1A also have congenital microcephaly, structural brain abnormalities, and intellectual disability (Møller et al, 2008; Ji et al, 2015). …”

Advancing the understanding of autism disease mechanisms through genetics

“…For example, LGDs in CHD8 and DYRK1A have been found in individuals with ID and ASD but as yet have never been observed in unaffected individuals, indicating high penetrance of these mutations 43,44 . Patients with these rare mutations were then extensively phenotyped to identify distinct syndromic subtypes 78–80 . In contrast, individual common variants indicate only a small risk for disease and cannot be used for diagnosis.…”