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/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.

Figures

Figure 1

Facial features, hand and feet abnormalities of individuals with DYRK1A SNVs, INDELs, and microdeletions. Note the sparse scalp hair, bitemporal narrowing, deeply set eyes, peri-orbital fullness, prominent nasal bridge and pointed nasal tip, prominent ears with underdeveloped ear lobes, variations of philtrum (short in P3 and P10, prominent and tented in P4, tented in P7), thin vermillion border of the upper lip, short chin with horizontal crease and/or chin dimple. P4 has slightly tapered fingers (STF), mild fetal finger pads (not shown), broad fingertips; P6 has STF, mild clinodactyly bilaterally (MCB), curved 4th toes on the left (CTL); P10, at ages 3 y.o. and 8.7 y.o., has STF, MCB, CTL; P11 has STF and small feet. P3 at ages 9.9 y.o., and 12 y.o.; P14 at ages 5 y.o. and 11 y.o. Photographs of P2, P5, P8, and P9 were not available for publication.

Figure 2

Brain magnetic resonance imaging (MRI) findings – T1 and T2 images. (a, b): normal brain architecture of a 5-year old. MRIs obtained at the following ages: P1 36 m.o.; P2 18 m.o.; P3 10 y.o.; P4 4.2 y.o., P6 17 m.o.; P7 21 m.o.; P8 6 y.o.; P10 35 m.o.; P11 16 m.o.; P12 25 m.o. P1a – hypoplastic pituitary gland (HPG), P1b – gliosis, P1c – small brain stem (SBS) indicated by prominent prepontine cistern; P2a – large ventricles (LV), white matter hypomyelination (WMH), P2b – hypoplastic (thin) corpus callosum (HCC); P3a – SBS, thinning upper cervical cord, P3b – thin optic chiasm (TOC), P3c – LV, HPG; P4a – LV, P4b – TOC, HPG, SBS, P4c – frontal lobe atrophy (FLA), prominent frontal horns, P4d-WMH, gliosis; P6a – HCC, SBS, P6b – LV, WMH; P7a – microcephaly (MC), P7b – mild LV, P7c – WMH, P7d – SBS, P7e – SBS; P8a – MC, HPG; P10ab – LV, SBS, brain atrophy and WMH, gliosis in periventricular regions (not shown); P11a – HPG (arrowhead), SBS (white arrow), P11b – HCC, P11c – FLA; P12a – MC, SBS, HPG; P12b – LV, FLA. Original MRIs were reviewed by a UCLA Pediatric Neuroradiologist (NS).

Figure 3

Schematic representation of all genetic alterations in this report and those previously reported in the literature. Upper panel: chromosome 21 cytoband (hg19); boxed area represents DSCR. Middle panel: 21q22.13 deletion in different patients (un-scaled illustration); gray: published microdeletions, as indicated by the author and year; black: five microdeletions including DYRK1A. The black box across the deletions shows the position of DYRK1A gene. Lower panel: DYRK1A single-nucleotide variants and small INDELs with the scheme of corresponding amino-acid changes; blue box: the 11 exons of the DYRK1A gene. The width of the box represents the number of nuclear acids; light blue box: two alternative splicing sites; black solid arrowheads: Nonsense or frameshift variants identified in our patients; gray solid arrowheads: nonsense or frameshift variants identified in cases from published literature; white arrowheads: missense variants identified in our patients; (*)asterisks: missense variant positions in normal individuals in EVS that are predicted to be damaging by PolyPhen2.

Figure 4

Features of the three missense variants identified in DYRK1A. (a) The pedigree of three families with missense variants. (b) The Sanger sequencing traces of two of these variants. (c) Amino-acid alignments at the variant position (red box) and surrounding bases across 16 species as indicated on the left. (d) Overview of the human DYRK1A protein structure (PDB ID: 4MQ1). The active site (inset) is sandwiched between the N-terminal (blue) and C-terminal lobes (red), which are connected by a short hinge segment (green). The three residues mutated in patients (Lys188, Leu245, and Leu295) and the ATP (modeled from PDB ID: 1ATP) are shown as ball-and-stick configuration colored by atom. Lys188 coordinates (black dashed lines) the α- and β-phosphates of ATP. (e, f) Steric clashes caused by variants of Leu295Phe and Leu245Arg in relation to the active site. (e) Leu295Phe variant (magenta) causes a clash with Leu248 (red). (f) Leu245Arg (magenta) causes a clash with Ile303 (orange) and Ile293 (orange).