Clinical phenotype of ASD-associated DYRK1A haploinsufficiency

Abstract

Background: DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms.

Methods: Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents.

Results: DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype.

Conclusions: Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background.

Keywords: Autism; Clinical phenotype; DYRK1A; Disruptive mutation; Genetic syndrome; Genetically defined subtype.

Fig. 1

Summary of DYRK1A gene variants. Schematic depicting the locations of disruptive variants (truncating, missense, and splice site mutations), copy number variations, and chromosomal rearrangements affecting DYRK1A. The ideogram of human chromosome 21 and isoform NM101395.2 coding sequence was obtained from the UCSC genome browser [54]. a NM101395.2 coding sequence with eight reported splice site mutations (presented in HGVS cDNA notation). Mutations below the sequence are UW-SNV participants, above are Pub-SNV mutation cases. b The DYRK1A protein (NP_567824.1) with truncating (red) and missense (blue) mutations (presented in HGVS notation). Mutations below the protein are UW-SNV cases, above are Pub-SNV mutation cases. c Copy number deletions and chromosomal rearrangements, including six deletions of entire gene, four partial deletions, five mosaic deletions, and four translocations/inversions (lightning bolt)

Fig. 2

Common dysmorphic features in UW-SNV patients with DYRK1A haploinsufficiency. a Facial features of eight UW-SNV patients with DYRK1A haploinsufficiency. Note common features across patients, including prominent brow with high anterior hairline, slightly upslanted palpebral fissures, retrognathic jaw, deep-set eyes with a hooded appearance, bitemporal narrowing, high nasal bridge with tubular-shaped, broad-tipped nose, and protruding ears. b Profiles of six UW-SNV patients. Note prominent brows with high anterior hairlines as well as low-set, posteriorly rotated ears in a subset of patients. c Ear abnormalities in four UW-SNV patients, including post-rotated and protruding ears with protruding thick and overfolded helices (i.e., outer fold of the ear). d Foot abnormalities in eight UW-SNV patients. Common features include proximal placement of the first toe, crooked toes, and syndactyly of the second and third toes. Frameshift, nonsense, and missense cases identified by HGVS protein notation; cases with splice site variants identified by HGVS cDNA notation

Fig. 3

Phenotypic features in total DYRK1A sample, DYRK1A sample ascertained for ASD, and idiopathic ASD samples. Bar graph presented frequencies of core phenotypic features observed in 75% or more of DYRK1A patients. Total DYRK1A sample (Pub-SNV, UW-SNV, Pub-CHR) and DYRK1A sample ascertained for ASD were compared to frequencies of features in idiopathic ASD samples (total and IQ < 70) using Fisher’s exact tests (p < 0.001)

Fig. 4

Quantitative phenotype of DYRK1A, idiopathic, and CHD8 samples. Scatterplots of core phenotypic features in UW-SNV DYRK1A sample, (n = 10), idiopathic subset matched for age and gender (randomly sample, n = 10), and CHD8 sample (n = 12). Dotted lines designate conservative averages for typical population. HC head circumference, FSIQ full-scale IQ, ADOS CSS calibrated severity score. Independent sample t tests comparing DYRK1A, idiopathic, and CHD8 groups, p value adjusted for multiple comparisons

Fig. 5

Contribution of familial genetic background to head circumference, ASD symptoms, and IQ. UW-SNV cases are presented with their unaffected mothers and fathers on three phenotypic measures: a head circumference (Z score, SD), b ASD symptoms (Social Responsiveness Scale T score), and c IQ (full-scale standard score). Affected children presented with significantly more severe phenotypes compared to both unaffected mothers and fathers using Wilcoxon rank sum tests (p < 0.001). Variability in parental phenotype corresponds to proband variation. Probands with smaller head sizes relative to other UW-SNV cases correspond to parents who also have smaller head size and vice versa. There are similar patterns in cognition, perhaps more pronounced for fathers, such that fathers with higher IQ have probands with higher IQ relative to other DYRK1A cases. Related to social responsiveness, higher parental scores (i.e., greater social impairment) correspond to probands with greater social impairment. Also, note the apparent wider range of IQ variability for fathers (SD = 14.99) relative to mothers (SD = 9.42) and the wider range of head circumference variability for mothers (SD = 1.81) relative to fathers (SD = 0.52)