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.

Electronic supplementary material
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Full text

R E S E A R C H Open Access
Clinical phenotype of ASD-associated
DYRK1A haploinsufficiency
Rachel K. Earl
1
, Tychele N. Turner
2
, Heather C. Mefford
3
, Caitlin M. Hudac
1
, Jennifer Gerdts
1
, Evan E. Eichler
2,4
and Raphael A. Bernier
1,5*
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)andparticipantsinanongoingstudy
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, DYRK1A, Genetic syndrome, Genetically defined subtype, Disruptive mutation, Clinical phenotype
Background
Autism spectrum disorder (ASD) is characterized by tre-
mendous clinical variability and causal heterogeneity.
Historical efforts to behaviorally subtype ASD have been
largely unsuccessful due to lack of meaningful treatment
implications by subtype and inadequate consensus re-
garding clinical phenotype [1, 2]. Recent efforts have tar-
geted the genetic causes of ASD to explore biologically
defined subtypes [3, 4]. Advances in genetic sequencing
technology have improved our ability to identify disease-
causing mutations [5]. Chromosomal abnormalities,
copy number variants (CNVs), and disruptive single
nucleotide variants (SNVs), including nonsense, frame-
shift, and splice site mutations, have been associated
with increased risk of ASD [6–9]. Most recently, work
relating ASD risk to de novo disruptive SNVs suggests
these single point mutations account for approximately
10% of ASD cases [6, 8]. These discoveries have
prompted a shift in ASD research; instead of using ex-
tensive phenotyping prior to sequencing ASD popula-
tions, researchers have begun by identifying genes of
* Correspondence: rab2@u.washington.edu;rab2@uw.edu
1
Department of Psychiatry and Behavioral Sciences, University of
Washington, CHDD Box 357920, Seattle, WA 98195, USA
5
Center on Human Development and Disability, University of Washington,
Seattle, WA, USA
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Earl et al. Molecular Autism (2017) 8:54
DOI 10.1186/s13229-017-0173-5
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interest in affected individuals and then exploring
phenotype in specific gene cohorts [10].
The application of this genetics-first approach to sub-
typing ASD has successfully identified similar medical,
behavioral, and dysmorphic features shared by individ-
uals with disruptive variants in high-confidence ASD
risk genes, such as CHD8,ADNP,SCN2A, and DYRK1A
(e.g., [11–13]). Dual-specificity tyrosine phosphorylation-
regulated kinase 1A, or DYRK1A, is a highly conserved
gene in the Down syndrome critical region of chromo-
some 21 [6, 14], and appears to play a major role in
brain development, specifically neurogenesis, neural
plasticity, and cellular death [15]. DYRK1A haploinsuffi-
ciency was initially identified for its role in intellectual
disability, which is clinically defined as childhood onset
of significant cognitive and adaptive impairment [16].
Recurrent disruptions to DYRK1A have been found in as
many as 0.5% of cases with ASD [14, 17]. In Drosophila
models, truncating mutations to DYRK1A (Drosophila
ortholog termed the Minibrain (Mnb) gene) result in
microcephaly, including intact but smaller brain struc-
tures [18]. Dyrk1A-null mouse models (−/−) displayed
growth deficiencies resulting in mid-gestational death
[19]. Mice heterozygous for Dyrk1A (+/−) survived to
adulthood but presented with reduced growth, develop-
mental delays, motor and learning difficulties, and atyp-
ical behaviors, including anxiety [19, 20]. A consistent
clinical phenotype appears in humans. Reported cases to
date have exhibited microcephaly and intellectual dis-
ability; other features, including seizures, speech and
motor delays, feeding difficulties, and distinct facial dys-
morphology, have been noted as well [13, 15, 21–24].
Studies relying on medical record review have reported
ASD diagnoses in up to 40% of cases with DYRK1A mu-
tations, but many remaining cases have features consist-
ent with ASD, such as stereotypies, reduced eye contact,
and social anxiety [15, 21]. Few studies have conducted
diagnostic evaluations of ASD and ASD-related symp-
toms as part of a clinical phenotyping battery. Diagnostic
rates may be as high as 88% when ASD is directly evalu-
ated as part of the study assessment process [13].
Literature on DYRK1A haploinsufficiency supports its
association with ASD risk and suggests a complex
phenotype that includes distinct dysmorphology as well
as cognitive, neurological, and medical impairments.
However, studies to date have only reported categorical
descriptions of phenotype, which note the presence or
absence of a common phenotype, such as ASD or no
ASD. Quantitative assessments of ASD-related features
in large cohorts and in relation to other ASD cohorts
have not been examined. While previously published
reports have noted an emerging phenotypic profile,
variability in clinical presentation remains. Measurable
data on medical, developmental, and behavioral
characteristics are needed to better understand small
variations in phenotype between individuals. Further-
more, varied clinical presentations of individuals with
DYRK1A mutations have yet to be examined in the con-
text of their familial phenotypic profile as a measure of
remaining genetic background. This approach has been
applied to other developmental disorders and to CNVs
associated with ASD, but has yet to be applied to disrup-
tive SNVs associated with ASD [25–28].
The aim of the proposed study was to examine a large
cohort of cases with DYRK1A mutations, provide a sum-
mary of phenotype, and compare recurrent medical and
behavioral features to (1) large idiopathic ASD samples
and (2) a cohort with disruptive mutations to a different
ASD-associated gene, CHD8. Alongside DYRK1A,CHD8
is one of the most recurrent genes with disruptive SNVs
implicated in ASD and provides a comparison group
ascertained in the same way as the cases with DYRK1A
mutations in this sample [6, 8]. Detection of phenotypic
differences between these two groups could inform un-
derstanding of different biological profiles of ASD and il-
luminate key features unique to each disrupted gene.
This study also explored the contribution of genetic
background to phenotypic variability among individuals
with disruptive DYRK1A mutations.
Methods
Participants
DYRK1A sample
Participants included 42 individuals with de novo,
disruptive, pathogenic SNVs (nonsense, splice site,
frameshift, and missense mutations) at the DYRK1A
gene. (Fig. 1; see Additional files 1 and 2 for full variant
information). The sample includes 10 individuals
assessed as part of an ongoing study at the University of
Washington (UW), including 7 new cases identified
through clinical genetic testing and 3 previously
published cases recruited from the Simons Simplex Col-
lection (see below). In addition to the 3 previously pub-
lished cases studied at UW, 32 other previously
published cases with disruptive SNVs were included in
the sample. All subjects were identified via clinical ex-
ome sequencing, or exome or targeted sequencing of re-
search cohorts ascertained for a diagnosis of ASD or ID.
Those seen at UW (UW-SNV group; n= 9 de novo
and n= 1 non-maternal; see Table 1 for variant informa-
tion [29]) completed standardized behavioral measures
and medical evaluations by clinicians naïve to gene
group membership as part of a study evaluating
individuals ages four and older with ASD-associated, dis-
ruptive mutations. Biological parents of the participants
were also characterized.
Thirty-two previously published cases of DYRK1A dis-
ruptive SNVs (Pub-SNV group) included 31 de novo
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cases and 1 non-maternal case [13, 15, 21, 22, 30–32]
with available medical history, physical features, and
diagnoses.
Additionally, the phenotype of 19 previously published
cases of de novo DYRK1A chromosomal rearrangements
(Pub-CHR group), including microdeletions and translo-
cations, was described and compared to those with
disruptive SNVs [21, 24, 33–39]. See Table 2 for partici-
pant characteristics for the 61 total DYRK1A sample
participants.
Comparison samples
Secondary data from an idiopathic subset of the Simons
Simplex Collection (SSC), a large sample ascertained for
ASD, were compared to the DYRK1A sample. The SSC
was a cohort of 2446 simplex families including a single
proband with ASD age 4–18, unaffected biological par-
ents, and any unaffected siblings [40]. Probands were in-
cluded in the idiopathic subset (n= 1981) if they had no
known disruptive SNVs or deleterious CNVs, as deter-
mined by sequencing efforts by Sanders and colleagues
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]. aNM101395.2 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. bThe 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. cCopy number deletions and chromosomal rearrangements, including six deletions of entire gene, four partial deletions, five mosaic
deletions, and four translocations/inversions (lightning bolt)
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in 2015, and not based on any phenotypic or behavioral
profile [8]. In order to account for high rates of ID seen in
the DYRK1A haploinsufficiency, a subset of the idiopathic
group with full-scale IQ below 70 (n= 487) served as an
additional comparison group. Also, a randomly selected
age- and gender-matched subset (n= 10) of the full idio-
pathic sample was compared to the subset of DYRK1A
cases assessed quantitatively at the UW. As part of the
SSC, probands were assessed on measures of neurocogni-
tive functioning, social communication behaviors, motor
skills, physical features (e.g., head circumference), and
medical history (measures described below).
Twelve individuals with disruptive SNVs at a different
high-confidence ASD risk gene, CHD8 (chromodomain
helicase-DNA-binding protein 8), participating in the
same UW characterization study and assessed by clini-
cians naïve to implicated gene disruption, served as a
comparison cohort matched on ascertainment approach.
Measures
Categorical assessment of diagnostic history and
developmental characteristics
Psychiatric and medical history, developmental milestones,
and physiological characteristics were gathered from Pub-
SNV and Pub-CHR cases. In addition to published data,
supplemental case reports detailing medical history and de-
velopmental trajectory were reviewed when available.
For UW-SNV study participants, a structured caregiver
interview, adapted from the SSC, was administered to
gather information about developmental, psychiatric,
and medical history. When caregiver-endorsed diagnoses
required additional clarification, medical records were
reviewed for confirmation. Using all available informa-
tion, psychiatric diagnoses were either confirmed or
newly diagnosed by a licensed clinical psychologist using
the Diagnostic and Statistical Manual of Mental Disor-
ders,5th Edition (DSM-5) [16]. For research purposes,
subjects were given an ASD diagnosis based on clinician
observation and parent interview using standardized in-
struments (gold-standard assessment tools described
below). A diagnosis of intellectual disability was given
when a subject displayed childhood onset of deficits in
both cognitive and adaptive functioning. When subjects
were under the age of 5 and had failed to reach cognitive
developmental milestones at the time of assessment, a
diagnosis of Global Developmental Delay was given. A
physical and dysmorphology exam was conducted by a
licensed medical geneticist.
Table 1 DYRK1A variant information for UW-SNV mutation patients
Patient Position Type of mutation cDNA Protein Inheritance
1 21:38865466 Splice site c.1098+1G>A –De novo
2 21:38845116 Frameshift c.143_144delTA p.Ile48Lysfs*2 De novo
3 21:38877833 Frameshift c.1491delC p.Ala498Profs*61 De novo
4 21:38868533 Frameshift c.1217_1220delAGAA p.Lys406Argfs*44 De novo
5 21:38862575 Nonsense c.763C>T p.Arg255* De novo
6 21:38877746 Frameshift c.1401delAinsGG p.Ile468Aspfs*17 De novo
7 21:38853064 Frameshift c.452dupA p.Asn151Lysfs*12 Not maternal
8 21:38862695 Missense c.883C>T p.Leu295Phe De novo
9 21:38862463 Splice site c.665-8_665-3delTCTTTC –De novo
10 21:38877590 Frameshift c.1248delA p.Lys416Asnfs*35 De novo
Variant information for UW-SNV patients using NCBI reference sequence for DYRK1A isoform NM_101395.2, GRCh37 (hg19) build version (Ensembl id:
ENST00000338785). This isoform was selected because it was the highest expressing isoform in human tissues in the GTEx database [https://gtexportal.org/home/
gene/DYRK1A]) [53]. Patients 1–3 were first identified through the Simons Simplex Collection, patients 4–10 underwent clinical genetic testing prior to research
participation. cDNA and protein (NP_567824.1) annotation follows HGVS guidelines
Table 2 Demographics
DYRK1A sample SSC idiopathic sample CHD8 sample
Disruptive SNVs CHR No disruptive SNVs or deleterious CNVs Disruptive SNVs
Pub-SNV UW-SNV Pub-CHR Total sample IQ < 70
Total N(male) 32 (22) 10 (4) 19 (9) 1981 (1705) 487 (407) 12(9)
Mean age in months (SD) 124.12 (128.85) 108.40 (69.12) 102.22 (88.06) 107.66 (42.34) 114.00 (44.00) 148.08 (64.56)
Participant demographics. SNV single nucleotide variant, Pub-SNV published disruptive SNV cases, UW-SNV UW study cases with disruptive SNVs, Pub-CHR
published chromosomal rearrangement, CNV copy number variant. Note that there are three overlapping individuals in the Pub-SNV and UW-SNV groups
ascertained from the Simons Simplex Collection. DYRK1A sample significantly differed from idiopathic ASD samples (total and IQ < 70) in gender ratio, χ
2
(1,
n= 2042) = 66.88, p< 0.001 and χ
2
(1, n= 548) = 36.25, p< 0.001, respectively. Samples did not significantly differ in age, p> 0.05. No significant differences in
age or gender for DYRK1A and CHD8 samples
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Quantitative assessment of DYRK1A UW-SNV (n= 10) and
CHD8 (n= 12)
Head circumference
Occipital frontal head circumference was measured and
standardized values calculated using a normative popula-
tion reference [41].
Cognitive functioning
Full-scale IQ was assessed in probands and unaffected
parents. Probands ages 4 years, 0 months to 17 years,
11 months were administered the Differential Abilities
Scales,2nd Edition [42]. Probands 18 and older, as well
as unaffected parents, were administered the Wechsler
Abbreviated Scales of Intelligence [43]. For all assess-
ments, IQ scores were generated using deviation (stand-
ard; mean = 100, SD = 15) or ratio scores (mental age
equivalent/chronological age × 100). Ratio scores were
derived using age equivalence values if standard scores
were not possible to calculate due to subject’s level of
functioning.
Adaptive functioning
Caregivers were administered the Vineland Adaptive Be-
havior Scales, 2nd edition (VABS-2) to measure adaptive
functioning across communication, daily living skills,
and social domains [44].
ASD-specific assessment
Research-reliable clinicians administered the appropriate
module of the Autism Diagnostic Observation Schedule,
2nd Edition (ADOS-2; [45, 46]) and Autism Diagnostic
Interview-Revised (ADI-R; [47]). ADOS calibrated sever-
ity scores, and items regarding age of first words and age
of first steps from the ADI-R were used in analyses. The
total Tscore from the Social Responsiveness Scale (SRS-
2; [48]) was used to quantify ASD-associated symptoms
in all UW-SNV family members.
Analytic approach
Categorical variables
Fisher’s exact tests were used to compare frequencies of
features commonly found for DYRK1A mutations across
disruptive SNV (Pub-SNV and UW-SNV) and chromo-
somal rearrangement (Pub-CHR) groups. These features
included intellectual disability, speech delay (defined as
first words after 24 months of age), motor deficits (e.g.,
delayed walking, poor coordination, abnormal gait),
ASD-related deficits (e.g., ASD diagnosis, stereotypic be-
haviors, anxious behaviors), feeding difficulties, seizures,
vision abnormalities, and microcephaly. The frequency
of most common features (defined as present in 75% or
more cases) was compared across DYRK1A and idio-
pathic ASD groups (total idiopathic sample and subset
with IQ below 70). Only characteristics specifically noted
in case reports were included in analyses; if a phenotypic
characteristic was not reported, it was treated as missing
for that individual. Total frequencies reflect cases with a
reported presence or absence of a given characteristic.
Quantitative variables
UW-SNV DYRK1A participants were compared to (1) a
randomly subsampled age and gender-matched subset of
the SSC idiopathic sample and (2) a cohort with disrup-
tive CHD8 mutations on domains of functioning
assessed quantitatively, including head circumference,
IQ, adaptive functioning, ASD severity (ADOS calibrated
severity score), age of first words (ADI-R), and age of
first independent steps (ADI-R). Independent sample t
tests were used to compare the DYRK1A, idiopathic, and
CHD8 groups, using the Bonferroni adjustment for mul-
tiple comparisons (p< 0.002).
Nonparametric Wilcoxon signed rank tests were used
to compare parental and proband phenotype for UW-
SNV participants in head circumference, IQ, and ASD
symptoms (SRS). Gene “effect size,”measured as the dif-
ference between parental and proband phenotype, was
calculated as follows:
Effect size ¼
Proband mean−Unaffected biparental mean
Unaffected biparental standard deviation
When both maternal and paternal data were available,
biparental means were calculated as the average of ma-
ternal and paternal scores. If only one parent’s data was
available, that parent’s score was used instead of a bipa-
rental mean.
Results
Clinical phenotype of DYRK1A
There were no significant differences between disruptive
SNV (Pub-SNV and UW-SNV) and chromosomal re-
arrangement (Pub-CHR) groups on frequency of pheno-
typic characteristics (Table 3). Language delay was noted
for 61/61 (100%); 21 individuals were nonverbal at the
time of their evaluation. Intellectual disability and/or
Global Developmental Delay (depending on age) were
reported in 60/61 (98%) cases. The presence of motor
difficulties, including delayed walking, abnormal gait,
and poor coordination, was noted for 52/53 (98%). A
common abnormal gait was observed across UW-SNV
participants, specifically a lilting gait with a forward lean
to the upper body, arms bent and held tight against the
body, and hands splayed. Feeding difficulties in infancy,
including poor suck, were observed in 51/54 (94%) of
those with reports of feeding abilities in early develop-
ment. Microcephaly, defined as head circumference two
or more standard deviations below the mean for age, ei-
ther primary (present throughout development) or
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acquired at a later age, was reported in 58/61 cases
(95%). Vision abnormalities were identified in 34/42
(81%) cases, including impairments such as strabismus,
astigmatism, optic nerve dysfunction, and corneal cloud-
ing. Febrile and non-febrile seizures were reported in
42/58 cases (72%).
Diagnoses of ASD were reported in 18/42 cases (43%),
suggesting elevated risk well above the general popula-
tion percentage of 1.5% [49]. The frequency increased to
42/61 cases (69%) when broadening the criteria to in-
clude ASD-related behaviors without a formal diagnosis,
such as stereotypic behaviors (e.g., complex motor man-
nerisms, repetitive and self-stimulatory behaviors), lim-
ited eye contact (reported in those without known
severe vision impairments), inappropriate laughter, and
limited social engagement. Anxious behaviors were re-
ported in 12/44 cases (27%), and hyperactivity was re-
ported in 14/43 cases (33%). Seven of the ten UW-SNV
cases were confirmed to have ASD; three who did not
meet diagnostic criteria presented with notable stereoty-
pies and socially anxious behaviors.
Co-occurrence of the seven most common phenotypic
features (reported in 75% or more of cases) was evalu-
ated: microcephaly, intellectual impairment, speech
delay, motor difficulties, feeding difficulties, vision ab-
normalities, and ASD. Fifty-two percent of the total
DYRK1A sample (32/61) possessed six or more features.
Sixty-nine percent (42/61) presented with six or more
features when the ASD category was broadened to in-
clude other behavioral difficulties, including stereotypic,
anxious, and hyperactive behaviors.
Facial dysmorphisms were reported in 50/51 (98%)
previously published cases (excluding UW-SNV cases
who were previously published, n= 3). Similar dys-
morphic facial features were observed in eight UW-SNV
cases who participated in a standardized medical exam
(five new cases, three previously published), including
deep-set eyes with a hooded appearance, slightly
upslanting palpebral fissures, bitemporal narrowing,
prominent brow with high anterior hairline, tubular-
shaped nose, prominent nasal bridge, retrognathic jaw,
and small chin (Fig. 2a). Additionally, prominent, low-
set, or malformed ears were also reported across cases;
4/8 UW-SNV cases presented with thick, overfolded ear
helices (Fig. 2b). Foot anomalies were also noted across
patients, including toe syndactyly (webbing of the toes),
arachnodactyly, crooked toes, and proximal placement
of the first toe (Fig. 2c). Observed commonalities in fa-
cial, ear, and foot characteristics in UW-SNV cases were
consistent with reports of previously published cases. In
the larger sample, spine or chest abnormalities, includ-
ing pectus excavatum and scoliosis, were reported in 13/
25 cases with documented skeletal observations.
Phenotypic comparisons of DYRK1A to idiopathic ASD
Rates of microcephaly, intellectual disability, speech
delay, motor difficulties, vision impairments, and feeding
difficulties were significantly higher in the total DYRK1A
group (Pub-SNV, UW-SNV, and Pub-CHR combined)
relative both to the full idiopathic SSC comparison co-
hort and the subset with IQ below 70 (Table 4; Fig. 3).
Table 3 Phenotypic characteristics of DYRK1A
Pub-SNV and UW-SNV (n= 42) Pub-CHR (n= 19) Total (n= 61)
Phenotypic characteristic NTotal % NTotal % NTotal % Sig (Fisher’s exact tests)
Intellectual disability or Global Developmental Delay 41 42 98 19 19 100 60 61 98 NS
Speech delay 42 42 100 19 19 100 61 61 100 NS
Motor difficulties 38 38 100 14 15 93 52 53 98 NS
Microcephaly 39 42 93 19 19 100 58 61 95 NS
Feeding difficulties 37 40 93 14 14 100 51 54 94 NS
Vision abnormalities 26 33 79 8 9 89 34 42 81 NS
Seizures 26 39 67 16 19 84 42 58 72 NS
ASD diagnosis 16 35 46 2 7 29 18 42 43 NS
Stereotyped behaviors 22 36 61 4 9 44 26 45 58 NS
Anxious behaviors 11 36 31 1 8 13 12 44 27 NS
Hyperactive behaviors 10 35 29 4 8 50 14 43 33 NS
Behavioral differences 35 42 83 7 19 37 42 61 69 NS
6+ symptoms including ASD 25 42 60 7 19 37 32 61 52 NS
6+ symptoms including broader behavioral difficulties 32 42 76 10 19 53 42 61 69 NS
Frequency of phenotypic features in cases with disruptive SNVs (Pub-SNV and UW-SNV) to DYRK1A, published chromosomal rearrangements (Pub-CHR) to DYRK1A,
and total combined cases. Totals reflect those with complete data. Groups did not significantly differ in gender ratio (Fisher’s exact test) or age (independent
sample ttest), p> 0.05. Fisher’s exact tests used for group comparisons, Sig significance, NS not significant
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Fig. 2 (See legend on next page.)
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The majority of the DYRK1A group (79%) displayed
five or more of these phenotypic features in combin-
ation. The percentages and group differences remain in
the subset of individuals with DYRK1A mutations ascer-
tained for an ASD diagnosis (n= 18, Fig. 3). Co-
occurrence of five or more features increased to 89% in
those with DYRK1A mutations ascertained for ASD.
Quantitative phenotype of DYRK1A
DYRK1A vs idiopathic ASD
Independent sample ttests revealed significant differ-
ences between UW-SNV and a matched idiopathic
group on measures of head circumference, cognitive
ability, and adaptive functioning (Table 5; Fig. 4). The
UW-SNV group had significantly smaller head circum-
ference (p< 0.001), significantly lower full-scale IQ
(p= 0.002), and significantly lower adaptive abilities
(p= 0.001) compared to the idiopathic group. There
were no differences between groups on autism symptom
severity (ADOS calibrated severity score), age of first
words, or age of first independent steps. Outliers
across the six phenotypic features of interest repre-
sented different UW-SNV individuals, highlighting the
variability that is observed when exploring the pheno-
type quantitatively.
DYRK1A vs CHD8
No significant differences were found between CHD8
and idiopathic groups. However, UW-SNV and CHD8
groups differed significantly in head circumference
(p< 0.001), such that DYRK1A cases had significantly
smaller head size than CHD8 cases. IQ, adaptive
functioning, autism symptom severity, age of first
words, and age of first steps were similar across
groups (Table 5; Fig. 4).
Contribution of genetic background
When comparing parental and proband head circumfer-
ence Zscore, the presence of a DYRK1A mutation
accounted for a 2.93 SD decrease in head size for pro-
bands. Wilcoxon signed rank tests showed that both
mothers and fathers exhibited significantly larger head
size, controlling for age and gender, compared to their
affected child (Z=−2.67, p= 0.008 and Z=−2.20,
p= 0.028, respectively (Fig. 5a)). When comparing ASD-
related symptoms, DYRK1A accounted for a 5.51 SD in-
crease in SRS total Tscore (more symptoms). Wilcoxon
signed rank tests showed that both mothers and fathers
display significantly lower SRS scores compared to their
affected child (Z=−3.62, p< 0.001 and Z=−3.41,
p= 0.001, respectively (Fig. 5b)). On measures of full-
scale IQ, DYRK1A accounted for a 6.09 SD decrease in
IQ for probands compared to biparental IQ. Wilcoxon
signed rank tests showed that both mothers and fathers
display significantly higher IQ compared to their affected
child (Z=−2.67, p= 0.008 and Z=−2.20, p= 0.028, re-
spectively (Fig. 5c)).
Discussion
This study of the DYRK1A haploinsufficiency phenotype,
compiling previously published and newly identified
cases, confirms a phenotype characterized by micro-
cephaly, intellectual disability, speech delay, motor diffi-
culties, feeding difficulties, and vision abnormalities. A
common facial gestalt included deep-set eyes with a
hooded appearance, slightly upslanted palpebral fissures,
tubular-shaped nose with pronounced broad tip, high
nasal bridge, prominent brow with high anterior hairline,
retrognathic jaw, and small chin. Dysmorphic feet, in-
cluding proximal placement of the first toe, syndactyly
of the second and third toe, and unusually long and/or
crooked toes, and protruding, post-rotated ears with
overfolded, thick helices were also commonly observed.
Those with de novo disruptive SNVs and chromosomal
rearrangements did not differ in clinical features.
Of those case studies where ASD was mentioned and/
or evaluated, 43% of probands received an ASD diagno-
sis. Among 15 cases who received gold-standard ASD
assessment, rates increased to 73%. Additionally, features
common to ASD, such as stereotypic and anxious behav-
iors, were noted in many cases where reference to an
ASD diagnosis was absent. This suggests rates of ASD in
DYRK1A cohorts may be higher in reality than reported
in the total sample of DYRK1A cases published to date.
There are several reasons for the potential underesti-
mated prevalence rate of ASD among published
DYRK1A cases. First, most previously published cases re-
lied on medical records, which varied greatly in the
(See figure on previous page.)
Fig. 2 Common dysmorphic features in UW-SNV patients with DYRK1A haploinsufficiency. aFacial features of eight UW-SNV patients with DYRK1A
haploinsufficiency. Note common features across patients, including prominent brow with high anterior hairline, slightly upslanted palpebral fis-
sures, retrognathic jaw, deep-set eyes with a hooded appearance, bitemporal narrowing, high nasal bridge with tubular-shaped, broad-tipped
nose, and protruding ears. bProfiles of six UW-SNV patients. Note prominent brows with high anterior hairlines as well as low-set, posteriorly ro-
tated ears in a subset of patients. cEar 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). dFoot 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
Earl et al. Molecular Autism (2017) 8:54 Page 8 of 15
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Table 4 Phenotypic comparisons of DYRK1A to idiopathic ASD
Total DYRK1A sample
(n= 61)
DYRK1A ascertained for
ASD (n=18)
SSC idiopathic ascertained
for ASD (n= 1981)
Sig (total DYRK1A
vs idio total)
SSC idiopathic ASD
with IQ < 70 (n=487)
Sig (total DYRK1A
vs idio IQ < 70)
Phenotypic characteristic N/total % N/total % N/total % N%
Intellectual disability or Global Developmental Delay 60/61 98 18/18 100 487/1974 25 p< 0.001 487/487 100 –
Speech delay 61/61 100 18/18 100 1173/1981 59 p< 0.001 343/487 70 p< 0.001
Motor difficulties 52/53 98 18/18 100 963/1981 49 p< 0.001 253/487 52 p< 0.001
Microcephaly 58/61 95 16/18 89 31/1958 2 p< 0.001 10/485 2 p< 0.001
Feeding difficulties 51/54 94 16/18 89 386/1981 19 p< 0.001 112/487 15 p< 0.001
Vision abnormalities 34/42 81 16/18 67 355/1981 18 p< 0.001 60/487 12 p< 0.001
5+ symptoms 48/61 79 16/18 89 6/1981 0.30 –5/487 1 –
Frequency of core phenotypic features (included if reported in 75% or more cases) observed in total DYRK1A sample (Pub-SNV, UW-SNV, and Pub-CHR) compared to frequency of same features in those with DYRK1A
mutations ascertained for ASD, a large sample of cases with idiopathic ASD from the Simons Simplex Collection (ascertained for ASD), and a subset of idiopathic cases with IQ < 70. Totals reflect those with complete
data. Fisher’s exact tests used to compare total DYRK1A sample to both idiopathic samples on each phenotypic characteristic; all group differences significant, p< 0.001. Sig significance
Earl et al. Molecular Autism (2017) 8:54 Page 9 of 15
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

detail provided and discussion of comprehensiveness of
prior evaluations; as such, it is unknown whether ASD
was either evaluated and ruled out, or not evaluated at
all. Second, it can be difficult to tease apart symptoms of
ASD from those of intellectual disability and speech im-
pairments without specialized training and experience
with differential diagnosis within developmental disabil-
ities, particularly in children with complex medical his-
tories. Additionally, establishing an ASD diagnosis may
not be the most pressing concern for families (and
perhaps providers) given the array of impairments and
medical conditions that often accompany children with a
DYRK1A mutation. As DYRK1A haploinsufficiency con-
tinues to be explored within ASD risk, these factors need
to be considered when determining rates in this
population.
In an effort to situate the DYRK1A phenotype in the
context of ASD, we found the DYRK1A group (Pub-
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)
Table 5 Quantitative phenotype and group differences between DYRK1A, idiopathic, and CHD8 groups
DYRK1A
(UW-SNV)
SSC idiopathic
subset
CHD8 t statistics DYRK1A
vs SSC
tstatistics DYRK1A
vs CHD8
tstatistics CHD8
vs SSC
Phenotypic characteristic Mean SD NMean SD NMean SD Nt d t d t d
Head circumference Zscore −3.62 2.17 10 1.21 0.39 10 1.76 2.9 11 6.94* 3.10 6.49** 2.84 NS –
Full-scale IQ 45.30 18.14 10 81.20 26.12 10 60.91 27.39 11 3.57* 1.60 NS –NS –
Overall adaptive functioning 54.80 9.04 10 70.50 9.40 10 65.00 18.49 12 3.81* 1.70 NS –NS –
Autism severity (ADOS CSS) 6.50 2.80 10 7.70 1.25 10 8.18 1.78 11 NS –NS –NS –
Age walked unaided 19.70 5.64 10 13.22 2.59 10 18.50 4.38 12 NS –NS –NS –
Age of first single words 45.14 22.82 7 17.50 7.92 10 25.17 28.01 12 NS –NS –NS –
Descriptives for phenotypic variables commonly impaired in DYRK1A haploinsufficiency for three groups: DYRK1 A (n= 10), SSC idiopathic subset randomly
samples and matched on age and gender (n= 10), and CHD8 (n= 12). Group comparisons using independent sample ttests between (1) DYRK1A and SSC
groups, (2) DYRK1A and CHD8 groups, and (3) CHD8 and SSC groups. *Significant differences between DYRK1A and idiopathic groups, p< 0.002; **Significant
differences between DYRK1A and CHD8 groups, p< 0.001. Independent sample tand Cohen’sdvalues provided when significant, pvalue adjusted for multiple
comparisons, NS not significant
Earl et al. Molecular Autism (2017) 8:54 Page 10 of 15
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SNV, UW-SNV, and Pub-CHR groups combined) exhib-
ited significantly higher incidence of key features com-
pared to those with idiopathic ASD: intellectual
disability, speech delay, motor difficulties, vision abnor-
malities, feeding difficulties, and microcephaly. Fre-
quency of these features also significantly differed
between the DYRK1A group and the comparison group
with idiopathic ASD and IQ below 70. This is consistent
with prior evidence that disruptive SNVs and CNVs
often result in significantly more impairing comorbidi-
ties than in idiopathic ASD [6, 8]. Notably, when those
with DYRK1A mutations who were originally ascertained
for an ASD diagnosis were compared to the idiopathic
group (also ascertained for ASD), the profile remains the
same. This provides further support that the phenotype
commonly exhibited in individuals with DYRK1A disrup-
tions and ASD is indeed distinct from idiopathic ASD.
The co-occurrence of five or more of these phenotypic
features in DYRK1A cases (79% of total sample, 89% of
those ascertained for ASD) provides support for further
exploration of DYRK1A haploinsufficiency in an individ-
ual presenting with concerns of ASD and this combin-
ation of phenotypic features.
Prior publications of DYRK1A mutation cases have re-
lied on categorical data to describe clinical phenotype.
Our exploration of a quantitative phenotype suggested
that DYRK1A haploinsufficiency is differentiable from
idiopathic ASD by measures of cognition, adaptive skills,
and head size and distinguishable from a different ASD-
associated gene mutation, CHD8 by head size. It is pos-
sible that further phenotypic differences exist which have
not been detected by current diagnostic tools given
limits to the level of resolution inherent in clinical as-
sessment. Markers relying on quantitative, brain-based
measures may reveal gene-specific profiles. For instance,
recent work highlights divergent information processing
systems for children with 16p11.2 CNVs [50] and
children with an early-emerging disruptive SNV [51].
Considering the intellectual disability associated with
DYRK1A haploinsufficiency, a passive, noninvasive
neuroimaging approach may help illuminate neuroendo-
phenotypes that link the behavioral phenotype to the
underlying neural mechanisms.
Exploring quantitative phenotype in UW-SNV partici-
pants illuminated phenotypic heterogeneity among indi-
viduals. While DYRK1A mutations significantly impact
functioning in a number of domains, the severity of im-
pairment varied among individuals. Family background
may, in part, contribute to this variability. While still ex-
ploratory, variability in parental phenotype corresponded
with variability observed in probands with DYRK1A hap-
loinsufficiency. Most striking were familial patterns on
measures of head circumference. Even with the range of
microcephaly, probands with the smallest head sizes
were related to parents with smaller head sizes com-
pared to other parents within the UW-SNV group.
Physiological characteristics are among the most highly
correlated between parents and children in typically
developing populations, ranging from 0.5 to 0.7 [52, 53].
Our findings suggest that, even in the presence of a de
novo, disruptive DYRK1A mutation, parental phenotype
may still impact their affected child’s presentation. Of
course, secondary genetic events, embryonic or early
developmental influences, and treatment must also be
considered as potential factors contributing to the
variability.
Our findings must be considered in the context of lim-
itations of this study. First, information available for
Fig. 4 Quantitative phenotype of DYRK1A,idiopathic,andCHD8 samples. Scatterplots of core phenotypic features in UW-SNV DYRK1A sample, (n= 10),
idiopathic subset matched for age and gender (randomly sample, n=10),andCHD8 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 ttests comparing DYRK1A,
idiopathic, and CHD8 groups, pvalue adjusted for multiple comparisons
Earl et al. Molecular Autism (2017) 8:54 Page 11 of 15
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previously published cases varied widely. While some
case reports provided detailed record of psychiatric his-
tory, others only included medical history, which also
varied in its extensiveness. Full assessment history was
unknown for previously published cases, raising ques-
tions whether phenotypic features left out of a case re-
port were previously ruled out and confirmed absent or
were not assessed. These variations highlight the import-
ance of consistency in phenotypic assessment across fu-
ture DYRK1A phenotype studies to ensure
comprehensive and accurate phenotyping efforts. Sec-
ond, those with DYRK1A mutations who participated in
the same quantitative assessment battery remain small
in number. Larger sample sizes are indeed needed to
better understand the quantitative phenotype of
DYRK1A haploinsufficiency and potential variability be-
tween affected individuals. Also, while comparison of
DYRK1A mutation cases to idiopathic ASD provides im-
portant confirmation of distinct comorbidities within
ASD, it is important to acknowledge that individuals in
the idiopathic group may, with future advances in our
understanding of the genetics of ASD, no longer be
identified as idiopathic. The idiopathic group analyzed in
this study likely represents a population with fewer syn-
dromic features than populations with ASD and other
genetic events. Thus, further studies and larger samples
of other ASD-associated gene mutations are needed to
further distinguish how the DYRK1A haploinsufficiency
phenotype differs from that of other disruptive gene
events. Future studies of this population should also aim
for greater specificity in phenotypic characterization in
efforts to better understand DYRK1A haploinsufficiency
as a unique clinical profile. Continued study of ASD-
associated genes, including DYRK1A, will allow for im-
proved understanding of ASD subtypes and inform fu-
ture approaches to personalized treatment.
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 (Zscore, SD), bASD symptoms (Social Responsive-
ness Scale Tscore), and cIQ (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)
Earl et al. Molecular Autism (2017) 8:54 Page 12 of 15
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Conclusions
DYRK1A haploinsufficiency results in a clinical phenotype
which includes microcephaly, intellectual impairment, the
presence of vision and motor difficulties, feeding difficul-
ties, language delays, and ASD risk. The DYRK1A profile
suggests a potential subtype of ASD. Despite a consistent
profile, quantitative assessment highlights heterogeneity in
the severity of impairments, with parental phenotype,
reflecting genetic background, as a likely contributor to
that variability among individuals.
Additional files
Additional file 1: Variant information for known de novo DYRK1A
mutation cases. Full variant information for previously published DYRK1A
variants and patients seen at UW. Previously published cases identified by
first author last name and UW cases denoted TXXX. Sheets organized by
variant type: snvs/indels, cnvs, mosaic variants, and translocations/
inversions. (XLSX 17 kb)
Additional file 2: Variant locations via UCSC Genome Browser.
Presentation of DYRK1A isoforms and variant locations for previously
published and UW cases. Figure generated in UCSC Genome Browser
[54]. (PDF 201 kb)
Abbreviations
ASD: Autism spectrum disorder; CHR: Chromosomal rearrangement
(including CNVs, translocations, and inversions); CNV: Copy number variation;
Pub-CHR: Previously published chromosomal rearrangements; Pub-
SNV: Previously published disruptive SNVs; SNV: Single nucleotide variant
(disruptive variants include nonsense, frameshift, splice site, and missense
mutations); UW-SNV: UW study participants with disruptive SNVs to DYRK1A
Acknowledgements
We would like to thank our funding sources and the families who took part
in this study.
Funding
This research was supported by the National Institute for Mental Health,
#R01MH100047 to R.A.B. and #R01MH101221 to E.E.E. E.E.E. is an investigator
of the Howard Hughes Medical Institute.
Availability of data and materials
The datasets used and analyzed during the current study are available from
the corresponding author on reasonable request.
Authors’contributions
RAB and EEE developed the study concept. EEE and TT performed genetic
sequencing, and TT consulted on the presentation of gene variant data.
Phenotypic data collection was carried out by RKE, HCM, and JG. RKE drafted
the manuscript, and RAB, TT, JG, CMH, and EEE provided critical revisions. All
authors approved the final version of the manuscript for submission.
Ethics approval and consent to participate
Written consent was obtained from participants, and all procedures were
approved by the University of Washington Institutional Review Board.
Consent for publication
Written informed consent was obtained from the participants for publication of
their individual details and accompanying images in this manuscript. The consent
form is held by the authors and is available for review by the Editor-in-Chief.
Competing interests
The authors declare that they have no competing interests.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Department of Psychiatry and Behavioral Sciences, University of
Washington, CHDD Box 357920, Seattle, WA 98195, USA.
2
Department of
Genome Sciences, University of Washington, Seattle, WA, USA.
3
School of
Medicine, University of Washington, Seattle, WA, USA.
4
Howard Hughes
Medical Institute, Seattle, WA, USA.
5
Center on Human Development and
Disability, University of Washington, Seattle, WA, USA.
Received: 30 June 2017 Accepted: 27 September 2017
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