European Journal of Medical Genetics 60 (2017) 212e216

Contents lists available at ScienceDirect

European Journal of Medical Genetics

journal homepage: http://www.elsevier.com/locate/ejmg

A de novo mutation in the X-linked PAK3 gene is the underlying cause

of intellectual disability and macrocephaly in monozygotic twins
Jozef Hertecant a, b, Makanko Komara c, Aslam Nagi a, Olfat Al-Zaabi d,
Waseem Fathallah e, Hong Cui f, Yaping Yang f, Christine M. Eng f, Mohammad Al Sorkhy g,
Mohammad A. Ghattas g, Lihadh Al-Gazali b, Bassam R. Ali c, *
a
Department of Paediatrics, Tawam Hospital, Al-Ain, United Arab Emirates
b
Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
c
Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
d
Fujairah Hospital, Fujairah, United Arab Emirates
e
Mafraq Hospital, Abu Dhabi, United Arab Emirates
f
Department of Molecular and Human Genetics, Baylor College of Medicine, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA
g
College of Pharmacy, Al Ain University of Science and Technology, Al-Ain, United Arab Emirates

a r t i c l e i n f o a b s t r a c t

Article history: Pathogenic variants in theP21 protein (Cdc42/Rac)-activated kinase 3gene (PAK3) lead to a rare non
Received 29 May 2016 syndromic X-linked intellectual disability. The protein encoded by this gene forms an activated complex
Received in revised form with GTP-bound RAS-like (P21), CDC2 and RAC1 proteins which then mediates a variety of cellular
17 January 2017
processes. So far, mutations in PAK3 gene have been reported in few families affected with intellectual
Accepted 18 January 2017
Available online 24 January 2017
disability associated with neurological manifestations such as speech defect, behavioral problem, brain
structural abnormalities, microcephaly and cerebral palsy. In this study whole exome sequencing
revealed a de novo likely pathogenic variant in PAK3 gene in monozygotic twins presented with intel-
Keywords:
de novo mutation
lectual disability, speech delay, behavioral problems and macrocephaly. Macrocephaly was noticed in our
X-linked patients from birth at 35 weeks of gestation. This aspect of the phenotype has not been previously re-
PAK3 ported in other documented cases with pathogenic mutations in PAK3 gene. Our ndings extend the
Intellectual disability phenotype of this disorder to include macrocephaly and offers further clues to the importance of the
Macrocephaly serine/threonine-protein kinase 3 (PAK3) protein in brain development and function.
2017 Elsevier Masson SAS. All rights reserved.

1. Introduction isolated trait or as part of a syndrome and therefore ID is subdivided

Intellectual Disability (ID) is one of the major burdens on health
care systems worldwide. It is dened as a signicant limitation both
in intellectual functioning and in adaptive behavior, covering social
and practical skills that originate before the age of 18 years
(Schalock et al., 2010). ID is a lifelong disability affecting about
2e3% of most populations presenting in infancy or early childhood.
Causes of ID are numerous, including environmental and genetic
factors but the majority of known causes are of genetic origins
(Daily et al., 2000; Bradinova et al., 2005). ID might occur as an
* Corresponding author. Department of Pathology, College of Medicine and
Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, United
Arab Emirates.
E-mail address: bassam.ali@uaeu.ac.ae (B.R. Ali).
into syndromic, in which intellectual decits are associated with
systemic abnormalities and nonsyndromic in which intellectual
decits, appear in the absence of other anomalies (Daily et al.,
2000; Bradinova et al., 2005; Moeschler and Shevell, 2006). Non-
syndromic ID accounts for 30e50% of all cases and it has been
estimated that about a quarter of the cases are caused by defects in
single genes (Daily et al., 2000; Bradinova et al., 2005). Variants in
several hundred genes have been identied as causing ID, but many
cases remain of unknown cause.
The prevalence of ID in males is approximately 30% higher than
in females (Herbst and Miller, 1980) suggesting a central role of
chromosome X located genes in cognitive functions and/or CNS
development (Schalock et al., 2010). To date, 122 genes have been
associated with X-linked intellectual disability (XLID) (Greenwood
Genetic Center, XLID Update March 2015; Stevenson et al., 2012).
One of the X-linked ID-causing genes is PAK3 which was discovered

http://dx.doi.org/10.1016/j.ejmg.2017.01.004
1769-7212/ 2017 Elsevier Masson SAS. All rights reserved.

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 J. Hertecant et al. / European Journal of Medical Genetics 60 (2017) 212e216
by Allen et al., in 1998. Subsequently, several other loss-of-function
variants and dominant negative function of PAK3 have been re-
ported in patients from diverse ethnic backgrounds with non-
syndromic X-linked intellectual disability (Bienvenu et al., 2000;
Gedeon et al., 2003; Peippo et al., 2007; Rejeb et al., 2008) and in
some cases with a more complex phenotypes of ID, skin defect and
brain structural abnormalities (Magini et al., 2014).
PAK3 encodes a member of the P21-activated family of serine/
threonine kinases (PAKs), which are downstream effectors for Rac/
Cdc42 and Rho GTPases. These proteins are known to regulate
multiple signal transduction pathways, including the MAPK
pathway (Slack-Davis et al., 2003; Beeser et al., 2005) and hence are
involved in controlling multiple intracellular processes including
proliferation, cell cycle progression and cytoskeleton remodeling
(Bokoch, 2003). In this article we report a de novo missense mu-
tation affecting a monozygotic twin presented with ID, speech
delay behavioral problems and macrocephaly. In addition, we
report variability in the clinical presentation in our patients
compared to patients reported in the literature with pathogenic
variants in PAK3.
2. Patients, material and methods
2.1. Patients, whole-exome sequencing and Sanger sequencing
This study has been approved by Al-Ain District Human
Research Ethics Committees (protocol number 10/09). We ascer-
tained a non-consanguineous family with two affected children
(Fig. 1A). Peripheral blood samples were collected in EDTA tubes
from the parents and both affected twins after obtaining informed
Fig. 1. A. Pedigree of the affected family. Dark lled colour represents the affected
siblings.
B. DNA Chromatogram showing the missense variant c.1279T > C in both twins
comparing to a non-carrier parent. (For interpretation of the references to colour in
this gure legend, the reader is referred to the web version of this article.)
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213
written consent. Genomic DNA was extracted using Flexigene DNA
kit (QiagenGmbh, Germany) following the manufacturers protocol.
Whole-exome sequencing for the rst twin was performed as a
service at the Baylor Medical Genetics Laboratories, Houston, TX,
USA (www.bcmgeneticlabs.org). Ilimunia platform was used for the
next generation sequencing. The mean coverage of the exome is
11e120X whereby 95% of the exome is covered at >20X. Variants
are ltered using various stringencies of minor allele frequencies, as
well as mutation databases and disease specic databases and a
team of certied molecular lab directors and medical directors
interpret the results based on disease phenotype. The nal ltration
identied candidate variants in DST, TTN and PAK3 genes. The
genomic DNA surrounding the identied candidate variant was
amplied using PCR. Primer sets were designed using Primer3
software (http://biotools.umassmed.edu/bioapps/primer3_www.
cgi) followed by purication of the PCR products using ExoSAP-IT
(USB Inc.) Sanger cycle sequencing was performed using 3130xl
Genetic Analyzer System (Applied Biosystems). Results were
analyzed based on NCBI reference sequence number NM_002578.
2.2. In silico analysis and protein stability
Prediction analysis using mutation taster (http://www.
mutationtaster.org/), PolyPhen2 (http://genetics.bwh.harvard.edu/
pph2/) and SIFT/Provean (http://sift.jcvi.org/) were used to assess
the potential effects of the variants (De Baets et al., 2012; Kumar
et al., 2009). The crystal structure of PAK3 homologous, PAK1,
was obtained from the protein data bank (PDB ID: 5DEY). The PAK1
structure was checked by Molecular Operation Environment (MOE)
(http://www.chemcomp.com) for any missing atoms using the
protein preparation module, which was also used to assign pro-
tonation states on ionizable groups and to set up partial charges on
the protein atoms. The Y429H mutation was generated via the
Residue Scan module in MOE. Accordingly, stability results of the
wildtype and mutated form of the protein are reported.
3. Results
3.1. Clinical description
The two affected children are monozygotic twins (Fig. 1A). The
non consanguineous parents have three healthy siblings who are
developmentally normal. The affected children were born after a
normal pregnancy of 35 weeks gestation. They were noticed to
have macrocephaly from birth. At birth, the weight of the rst twin
was 2.65 kg (P50), length was 47 cm (P50e75) and the head
circumference was 34.5 cm (P90). The weight of the second twin
was 3.11 kg (P90), length was 57 cm (above P97) and head
circumference was 35.3 cm (P97). We evaluated them at the age of
nearly 4 years. The rst twin did not speak at all in spite of a normal
hearing test. Reactive smile was only noticed at the age of 2 years.
He sat alone by the age of 9 months and started to walk at the age of
2 years and 9 months but still could not jump, run or walk upstairs
without support. He seemed to have autistic features as he did not
make eye contact and did not interact with his sibling. However, by
history, he does not have other typical features of autism, except
that he is unusually scared of loud noises, such as those of vacuum
cleaners and blenders. These get him very agitated and make him
cry and shout. He is not hyperactive and mainly plays with I-pads
and mobile phones. He watches cartoons on them all the time and
is much less interested in other activities. He sometimes gets
temper tantrums if he does not get what he wants. He accepts
nearly all the food his mother prepares, as long as it is soft but
refuses most fruits as well as meat. He does not eat or drink by
himself, the mother has to feed him and put the drinking glass to
214 J. Hertecant et al. / European Journal of Medical Genetics 60 (2017) 212e216

Fig. 2. A. model representing PAK3 protein. The sequence shows the functional domains CRIB and kinase domain. p. Y427H is located at the kinase domain.
B. Alignment of the amino acid sequence of PAK3 gene surrounding the p. Y427H variant. The tyrosine at position 427 is highly conserved.

his mouth. He sleeps well at night for about 10 h and not during the
day. There are no stereotypical or repetitive movements, he is not
overly aggressive and there is no history of self-injury. On physical
examination, his weight was 18.6 kg (P75-90), length 102 cm (P50-
75) and head circumference 54.5 cm (above P 97). The BMI was 17.9
(P95). The child was agitated and uncooperative. He did not interact
but was able to concentrate on his iPad for a long time. There were
no obvious dysmorphic features. Neurological examination showed
mild axial hypotonia with preserved deep tendon reexes. Motor
exam and gait were otherwise normal. The rest of the physical
exams were normal. The following investigations were also
normal: microarray and CDG screen by transferrin electrophoresis
and brain MRI was also normal with no malformations.
The second twin also does not speak, although he vocalizes.
According to the mother his development was a bit slower than his
brother's but only by a few weeks. Motor delay was rst suspected
by the age of 6 months. He could sit alone by the age of 9e10
months and started to take a few steps by the age of 18 months.
Independent walking was only achieved by the age of 2 years and 9
months. He still could not jump, run fast or walk upstairs without
support. Reactive smile was achieved very late, after the age of 2
years. He seemed to have autistic features as he did not make eye
contact and did not interact with his sibling. Other obvious typical
feature of autism is that he gets very scared of loud noises and
reacts to them in the same way as his twin brother, except that at
those times he also covers his ears. There are no typical anxieties,
obsessions or repetitive behaviours. He accepts most soft food,
including several types of fruit but tends to refuse meat. He has the
same, normal sleeping pattern as his brother, has the same interests
and activities and also gets similar temper tantrums if he does not
get what he wants. However, otherwise he is not unusually
aggressive and there is no reported self-injury. His weight and
length were 17.5 kg (P75-90) and 101 cm (P25-50), respectively. The
head circumference was 54 cm (above P 97) and BMI was 17.2 (P85-
90). The child was difcult to examine but a bit more cooperative
than his brother. He did not interact but was focussing on his iPad
the whole time. There were no obvious dysmorphic features.
Neurological examination showed mild axial hypotonia with pre-
served deep tendon reexes. Motor exam and gait were otherwise
normal. The rest of the physical exam was normal. The following
investigations were also normal: microarray and CDG screen by
transferrin electrophoresis and brain MRI was also normal with no

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 J. Hertecant et al. / European Journal of Medical Genetics 60 (2017) 212e216 215

brother and the absence in the parental samples which indicates a

de novo origin for this variant. This substitution leads to a non-
synonymous change (Tyrosine to Histidine) at amino acid posi-
tion 427 (Fig. 2A). The variant was neither found in the 1000
Genome database nor the ExAC database.

3.3. The p.Y427H variant of affectsPAK3 protein stability

In silico analysis prediction indicated that the variant is disease

causing (Mutation Taster). Polyphen 2 and SIFT/Provean predicted a
damaging effect (Polyphen2: 1.0; SIFT: 4.77/0.00 scores). More-
over, the variant is also predicted, based on the structure homology
analysis using the Residue Scan module in MOE to cause a reduc-
tion in protein stability by 5.55 kcal/mol (Table 2).

4. Discussion

We report here a de novo missense variant in an X-linked gen-

Fig. 3. The crystal structure of PAK1 homologous, PAK3, shown in cartoon. Tyr429
(grey sticks) forms hydrogen bonding with the backbone amide of Glu467 (grey sticks).
Hydrogen bonding is shown in orange with distance in angstrom. The side chain of
His429 (orange sticks), featuring in the Y429H mutation, appears to be not able to form
the same hydrogen bond with Glu467. (For interpretation of the references to colour in
this gure legend, the reader is referred to the web version of this article.)
malformations.
The head circumferences of several family members were
measured. The father's was 55.3 cm (P55), the mother's 54.3 cm
(P49). The oldest brother had a head circumference of 53 cm at the
age of 12 years (P23) and the second brother had a head circum-
ference of 54.7 cm at the age of 10 years (P87).
3.2. Whole-exome sequencing identied a de novo hemizygous
c.1279T > C (p.Y427H) variation a highly conserved catalytic
domain of PAK3
Whole-exome sequencing identied a hemizygous single
nucleotide substitution (c.1279T > C; NM_002578) at exon 16 in
affected child in the X-linked PAK3 gene (Fig. 1B). Sanger
sequencing conrmed the presence of the variant in the twin
ePAK3 in monozygotic twins presenting with ID and macrocephaly.
The variant is located at a highly unique residue of the PAK3 pro-
tein. Insilico analysis predicted the variant to be likely pathogenic.
Also, we performed structural modelling of PAK3 based on the
homology model for PAK1 and the results showed a disturbance in
the hydrogen bonding between the mutated residue and Glu at
position 467, hence reducing protein stability (Fig. 3). Since PAK3
mutations were rst described as a cause of non-syndromic X-
linked intellectual disability (Allen et al., 1998), several cases have
been reported with some variability in their phenotypic and clinical
presentations. In reviewing the literature it can be said that loss of
function variants in PAK3 have been reported in most of the well
documented cases and caused instability of PAK3 associated with
no syndromic ID and mild phenotype variability (Allen et al., 1998;
Bienvenu et al., 2000; Gedeon et al., 2003; McMichael et al., 2015;
Peippo et al., 2007; Rejeb et al., 2008). In addition, Magini et al.,
2014 has reported PAK3 missense variant that segregated with a
more complex phenotype including ID, skin defect, brain structural
abnormalities and dysmorphic features and demonstrated to cause
a dominant negative effect of PAK3.
Table 1 summarizes the reported cases and associated pheno-
types. Our patients have several common features that have been
described previously including ID, motor delay, speech and
behavioral problems. What makes our patients more unique is their
well-documented macrocephaly, which was present since birth
and has not been described previously in this disorder, although
microcephaly has been described in several cases. It is well docu-
mented that macrocephaly can be present in intellectually disabled
individuals and autism (Williams et al., 2008). Although our pa-
tients have some autistic feature, it has been known that macro-
cephaly seen in autism usually manifest from 1 to 3 years of age and
is not present at birth as seen in our paediatric twins (Williams
et al., 2008) which indicate a likely pathogenic effect of PAK3
gene mutations found in this study.

Table 1
Summary of reported pathogenic variants in PAK3 genes and associated phenotypes.

Variant Associated phenotypes References

p.R67C ID, development delay (Bienvenu et al., 2000)

p.A365E Mild ID, neuropsychiatric disorders (Gedeon et al., 2003)
p.K389N ID, brain structural abnormalities, skin alterations and dysmorphic features (Magini et al., 2014)
p.R419* ID, microcephaly (Allen et al., 1998)
p.W446S ID, microcephaly, behavioral problems, development delay and seizures (Peippo et al., 2007)
p.R493C cerebral palsy (McMichael et al., 2015)
p.G92VfsX35 ID, mild dysmorphic features, seizure, behavior disturbances, secondary microcephaly (Rejeb et al., 2008)
p.Y427H ID, macrocephaly, behavioral and development abnormalities This study

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Table 2
Stability results of PAK1 homologous, PAK3, produced by MOE.
PDB Mutation Stability (kcal/mol) DStability (kcal/mol)
5DEY Y429Y 9.65 0.00
5DEY Y429H 4.10 5.55
The P21-activated kinases (PAKs) are a family of serine/threo-
nine kinases involved in signal transduction and cellular regulation.
They are involved in cytoskeletal dynamics, cell motility, gene
transcription, and cell cycle progression. PAK3, a serine/threonine
protease is among the genes known to cause non-syndromic forms
of ID due to the role of their products in Rho GTPase pathway which
is important in vesicular trafcking in dendritic spines and cyto-
skeleton organization (Kaufman et al., 2010). Brain size is highly
sensitive and any minor change in the rate of neurogeneration can
lead to increase in cortical surface area which can result in mac-
rocephaly (Caviness et al., 1995; Caviness, 2003).
Our study is the rst to describe a de novo variant in PAK3 gene
in monozygotic twins causing ID spectrum disorders associated
with macrocephaly. Results of the current study support previous
ndings and provide further delineation of the reported pheno-
types associated with loss of PAK3. These ndings may provide
further insight into the role of PAK3 in cellular mechanisms un-
derlying neurodevelopment and brain function.
Conict of interest
All authors declare no conict of interest.
Acknowledgments
We would like to thank the patients and their family for
participating in this study. Laboratories of BRA and LA are funded by
the United Arab Emirates University (Grant Number 31M187).
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