RESEARCH ARTICLE
Duplication at Xq13.3–q21.1 With Syndromic
Intellectual Disability, a Probable Role for the
ATRX Gene
Francisco Martı́nez*, Mónica Roselló, Sonia Mayo, Sandra Monfort, Silvestre Oltra,
and Carmen Orellana
Unidad de Genética y Diagnostico Prenatal, Hospital Universitario y Politécnico La Fe, Valencia, Spain
Manuscript Received: 13 July 2013; Manuscript Accepted: 4 November 2013
Here we report on two unrelated male patients with syndromic
intellectual disability (ID) due to duplication at Xq13.3–q21.1, a
region of about 6 Mb and 25 genes. Among these, the most
outstanding is ATRX, the causative gene of X-linked alpha-
thalassemia/mental retardation. ATRX belongs to the growing
list of genes implied in chromatin remodeling causing ID. Many
these genes, such as MECP2, are dose-sensitive so that not only
deletions and point mutations, but also duplications cause ID.
Both patients have severe ID, absent expressive speech, early
hypotonia, behavior problems (hyperactivity, repetitive self-
stimulatory behavior), postnatal growth deficiency, microceph-
aly, micrognathia, cryptorchidism, low-set, posteriorly angu-
lated ears, and downslanting palpebral fissures. These findings
are also usually present among patients with loss-of-function
mutations of the ATRX gene. Completely skewed X inactivation
was observed in the only informative carrier mother, a constant
finding among female carriers of inactivating point mutations of
this gene. Participation of other duplicated genes cannot be
excluded; nevertheless we propose that the increased dosage
of ATRX is the major pathogenic mechanism of this X-linked
disorder, a syndrome reminiscent of MECP2 duplication.
Ó 2014 Wiley Periodicals, Inc.
Key words: XLID; autism; hyperactivity; MECP2; array CGH
INTRODUCTION
About 10% (95% confidence interval, 7.1–12.5%) of patients with
X-linked intellectual disability (XLID) carry pathogenic copy num-
ber variants of more than 100 kb in the X chromosome [Froyen
et al., 2007; Madrigal et al., 2007; Whibley et al., 2010]. These
deletions and duplications usually involve many genes, so that
the contribution of each individual gene to XLID remains unclear.
The abnormal dosage of specific genes, and more particularly
the dosage gains, has rarely been demonstrated as causal. In the
X chromosome, duplications of the PLP gene [Inoue et al., 1996],
MECP2 gene [Van Esch et al., 2005], and HUWE1 gene [Froyen
et al., 2012] constitute, so far, the few exceptions of pathogenic
overexpression. When a gene is dose-sensitive, both duplications
and deleterious mutations of the same genes may lead to different
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article:
Martı́nez F, Roselló M, Mayo S, Monfort S,
Oltra S, Orellana C. 2014. Duplication at
Xq13.3–q21.1 with syndromic intellectual
disability, a probable role for the ATRX
gene.
Am J Med Genet Part A 164A:918–923.
phenotypes, although with resembling clinical characteristics.
These include the duplication of the 22q11.2 region [Ensenauer
et al., 2003], the duplication of the Williams syndrome region
[Orellana et al., 2008], Wolf-Hirschhorn region [Roselló et al.,
2009] or duplication of the CDH7 gene, whose loss-of-function
mutations cause CHARGE syndrome [Monfort et al., 2008]. Thus,
clinical similarities with known monogenic conditions can help
in the elucidation of the particular gene(s) implicated in the
phenotype caused by genomic duplications.
X-linked alpha-thalassemia/mental retardation syndrome
(ATR-X syndrome, OMIM #301040) is one of the growing list
of syndromes due to loss-of-function mutations in genes implied in
chromatin remodeling: that is, Rett (MECP2), Rubinstein–Taybi
(CREBBP), Coffin-Lowry (RPS6KA3), Sotos (NSD1), or Coffin-
Siris (components of the SWI/SNF complex), among others
[reviewed in Kramer and van Bokhoven, 2009]. ATR-X syndrome
is characterized by profound mental retardation, a characteristic
The authors declare no conflict of interest.
Grant sponsor: Plan Nacional IþDþI 2008–2011 (ISCIII -Subdirección
General de Evaluación y Fomento de la Investigación); Grant number:
PI11/00389; Grant sponsor: FEDER (Fondo Europeo de Desarrollo
Regional, EU); Grant sponsor: Fundación Ramón Areces.

Correspondence to:
Francisco Martı́nez, Unidad de Genética y Diagnostico Prenatal,
Hospital Universitario y Politécnico La Fe, Valencia, 46009, Spain.
E-mail: francisco@gva.es
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 23 January 2014
DOI 10.1002/ajmg.a.36371
918
MARTÍNEZ ET AL.
facial appearance, skeletal abnormalities, autistic behavior and mild
alpha-thalassemia not always present. It is caused by a mutation in
the ATRX gene (Xq13), which encodes ATRX protein, a member of
the SNF2 family of chromatin-remodeling proteins [Gibbons
et al., 1995]. Perturbation in DNA methylation in the rDNA genes
was reported in ATR-X patients, and ATRX protein is presumed to
be involved in the establishment and maintenance of DNA meth-
ylation. Based on its various clinical phenotypes, the expression of
many genes, including alpha globin genes, seem to be abnormally
regulated in ATR-X patients [Law et al., 2010].
Here, we describe two unrelated male patients with a similar clinical
presentation due to duplication at Xq including the ATRX gene.
MATERIALS AND METHODS
Genomic DNA from the patients and other relatives was isolated
from peripheral blood using QIAamp DNA Mini Kit, and the
Qiacube extractor (QIAGEN, Hilden, Germany). DNA quality
and concentration was measured using the NanoDrop ND-1000
Spectrophotometer (NanoDrop Technologies, Wilmington, DE)
and stored at 20˚C. Informed consent was obtained from all the
participants in the study.
Whole genome dosage analysis was performed by array-CGH
(44K oligo array G4410B, Agilent Technologies, Santa Clara, CA)
with an average oligonucleotide spacing of 43 kb. Array hybridiza-
tion and scanning were performed following the manufacturer’s
specifications. The data were analyzed using the DNA analytics 4.0
software (Agilent Technologies).
The X-chromosome inactivation pattern was assessed as de-
scribed elsewhere [Allen et al., 1992]. Two aliquots of 30 ng of
genomic DNA were digested at 37˚C for 1 hr with either 5 units of
RsaI or the methylation-sensitive restriction enzyme HpaII (Fer-
mentas, Vilnius, Lithuania), followed by heat inactivation at 94˚C
for 4 min. Both digestion products were then used as templates for
PCR amplification of the (CAG)n microsatellite repeat in the first
FIG. 1. Frontal and lateral view of Patient 1.
919
exon of the androgen receptor gene. PCR products were analyzed
on an ABI-PRISM3130xl genetic analyzer (Applied Biosystems,
Foster City, CA).
RESULTS
Patient 1 (Fig. 1) is the second child of non-consanguineous parents.
He was born at 38 weeks by cesarean for fetal distress, with a low birth
weight (2,100 g) and hypotonia; occipitofrontal circumference
(OFC) 34 cm; birth length 44 cm. Currently he is 14 years old
and shows severe psychomotor delay without speech or autono-
mous walking; he was not able to sit until age 10 years. He also
developed periods of aggressiveness and autistic traits: bruxism,
head stereotypes, biting fingers, lack of interest in other children, etc.
Array-CGH analysis revealed a 12.6 Mb gain at q13–q21.1 (po-
sition of first and last duplicated probes chrX:65815490–78426724;
hg19) which includes at least 13 different XLID genes: OPHN1,
IGBP1, DLG3, MED12, NLGN3, HDAC8, SLC16A2, ZDHHC15,
ATRX, MAGT1, COX7B, ATP7A, and PGK1 (Fig. 2). This duplica-
tion was inherited from his mother, his only maternal aunt was not a
carrier. The mother was not informative for the (CAG)n microsat-
ellite marker in the AR gene, so that the X-inactivation pattern could
not be determined.
Patient 2 was born with a normal birth weight (3,200 g) after a
normal pregnancy and delivery to non-consanguineous parents. He
showed hypotonia and underwent surgery for cryptorchidism. He
walked independently at 3 years; speech is severely impaired with a
vocabulary limited to a few words. He also has periods of hyperactivity
and aggressiveness. At 8 years, he had a height of 122 cm (less than
10th centile), weight of 32 kg (90th centile) and microcephaly (OFC
less than 3rd centile). NMR examination revealed ventriculomegaly
and enlarged cortical sulci. Results of laboratory examinations, such as
metabolic screen of blood and urine or EEG, were normal.
On array-CGH he had a large, 18.7 Mb duplication at Xq13.2–
q21.31 (chrX:72433198–91125471), a region that contains 9 known
920
FIG. 2. Array-CGH results from patients carrying Xq12-q13 duplication (adapted from UCSC; hg19). From top to bottom, schematic view of the
chromosome; duplications mapped by array CGH; Refseq genes; detailed view of the overlapping region.
XLID genes SLC16A2, ZDHHC15, ATRX, MAGT1, COX7B,
ATP7A, PGK1, BRWD3, and ZNF711 (Fig. 2). This duplication
was inherited from his normal mother. X inactivation study in the
mother showed a 100% inactivation of the X-chromosome with the
duplication.
DISCUSSION
Lugtenberg et al. [2009] identified a de novo 7 Mb duplication at
Xq13.2–q21.1 in a patient with severe intellectual disability (ID)
and other anomalies. The phenotype of this patient was similar to
that of other 10 previously reported patients with cytogenetically
visible chromosomal duplications of this region, establishing a
phenotype of severe ID, short stature, and genital abnormalities.
Our patients have most of the manifestations of this phenotype. On
the other hand, only two duplications of 16 and 0.33 Mb
(nssv583735 and nssv579220) spanning the ATRX gene are
reported in the International Standards for Cytogenomic Arrays
consortium [Miller et al., 2010]; clinical details are not available.
The overlapping region in our patients and that reported by
Lugtenberg et al. [2009] encompasses 7 XLID genes: SLC16A2,
ZDHHC15, ATRX, MAGT1, COX7B, ATP7A, and PGK1 (Fig. 2). A
clinical comparison of patients with mutations in these genes allows
a phenotype–genotype correlation (Table I). Many clinical aspects,
such as genital anomalies, midface hypoplasia, micrognathia, low-
set, small and/or everted ears, ptosis, low nasal bridge, downturned
corners of mouth, short and thin upper lip, or prominent lower lip,
are not reported except for ATRX. Postnatal growth deficiency is
reported only in some COX7B patients, who on the other hand have
mild psychomotor delay or normal intellectual abilities [Indrieri
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
et al., 2012]. The MAGT1 and ZCCHC15 genes have recently been
questioned to cause ID [Piton et al., 2013].
Conversely, the clinical similarities between the patients with
Xq13.3–q21.1 duplication and those with ATRX mutations are
striking. Both conditions not only share neurologic, genital, and
growth anomalies consequences, but also minor anomalies such as
midface hypoplasia, low-set and posteriorly rotated ears, ptosis, low
nasal bridge, etc. However other findings are opposite, such as
upslanting versus downslanting palpebral fissures or dolichoceph-
aly versus plagiocephaly. An effect on the same domains, some in
opposite directions, has also been reported in other reciprocal
duplication of microdeletion syndromes [Orellana et al., 2008].
We agree with Lugtenberg et al. [2009] that duplication of the ATRX
gene is the main pathogenic mechanism for this XLID phenotype,
without ruling out the possible contribution of neighboring genes.
Overexpression of ATRX gene in the mouse gives rise to neuro-
developmental defects and growth retardation. A high incidence of
embryonic and perinatal death was observed, probably due to a
several-fold overexpression. Mice that survived had a high inci-
dence of seizures, compulsive behavior, and mild craniofacial
anomalies such as a short broad snout [Bérubé et al., 2002], clearly
reminiscent of the findings in the Xq13–q21 duplication patients.
This would be a similar situation to that of the MECP2 gene,
where loss-of-function mutations cause Rett syndrome, while its
duplication gives rise to a different entity with common clinical
findings [Amir et al., 1999; Van Esch et al., 2005]. MECP2 is a
methyl-CpG-binding protein that physically interacts with ATRX,
targeting the C-terminal helicase domain of ATRX to heterochro-
matic foci in a DNA methylation-dependent manner. The localiza-
tion of ATRX is disturbed in neurons from Mecp2-null mice [Nan
TABLE I. Clinical Comparison among Patients with Xq13.2-q21.1 Duplication, ATRX Mutations and other Syndromic XLID Genes Contained in the Common Duplicated Region
(Adapted from Online Mendelian Inheritance in Man (OMIM) Webpage)
MARTÍNEZ ET AL.

Mutations in syndromic
XLID genes
Lugtenberg Previously published
Patient 1 Patient 2 et al. [2009] patients (a) ATRX SLC16A2 ZDHHC15 COX7B ATP7A PGK1
Postnatal growth þ þ þ 10/10 þ – – 2/4 IUGR –
deficiency
Microcephaly þ þ 10th centile 8/10 þ þ – þ þ –
Head (other)  Plagiocephaly Brachycephaly NR Dolichocephaly – – – Brachycephaly –
Plagiocephaly
Midface hypoplasia þ  þ 6/6 þ     
Bitemporal narrowing þ   NR þ þ    
Micrognathia þ þ þ 3/6 þ     
Low-set ears þ þ þ 3/9 þ     
Small ears þ   2/9 þ     
Everted ears  þ  NR þ     
Posteriorly þ þ þ NR þ   1/4  
rotated ears
Epicanthal folds    6/7 þ  þ   
Hypertelorism þ   2/5 þ   þ  
Palpebral fissures Downslanting Downslanting Downslanting 6/7 Upslanting   Upslanting  
Ptosis þ  þ 5/8 þ     
Low nasal bridge þ   9/9 þ     
Down-turned   þ 8/9 þ     
corners of mouth
Short, thin upper lip þ   NR þ     
Prominent lower lip  þ  NR þ     
High-arched palate   þ 3/3 þ  þ   
Hypoplastic genitalia þ  þ 6/9 þ     
Cryptorchidism þ þ þ 8/9 þ     
Skeletal findings (Spine) Kyphoscoliosis  Pectus excavatum, Pectus excavatum, Kyphoscoliosis Pectus excavatum,    
broad torax broad torax (6/6) broad, scoliosis
Digital findings   Clinodactyly Clinodactyly Clinodactyly  þ 1/4  
brachydactyly (5/6) brachydactyly
Mental retardation, severe þ þ þ 10/10 þ þ þ  þ Variable
Expressive speech absent þ þ  NR þ þ þ  þ 
Hypotonia þ þ þ 6/10 þ þ    
Behavioral manifestations Repetitive self- Hyperactivity Impaired social 4/5 Repetitive Irritability  ADHD  Emotional
stimulatory bruxism aggressiveness interaction self-stimulatory instability
hyperactivity…
þ, Present; , absent; NR, not reported; ADHD, attention deficit hyperactivity disorder; IUGR, intra uterine growth restriction; (a) Revised by Lugtenberg et al. [2009].
921
922
et al., 2007]. These findings suggested that disruption of MECP2-
ATRX interaction leads to pathologic changes that contribute to ID.
Consequently, it is tempting to speculate that a misbalance by
overexpression of any of these partners would equally lead to
developmental disorders.
The concomitant microduplications of MECP2 and ATRX in
male patients with severe ID in one family [Honda et al., 2012] were
not quite different than those usually found in patients with MECP2
duplication, except that the proband was found to have cerebellar
atrophy, with many of the clinical features common to both
duplication syndromes. These patients did not show some char-
acteristics associated with duplications of ATRX, such as short
stature or mid-face hypoplasia. It is possible that the concomitant
(and balanced) overexpression of both genes might mitigate some
symptoms.
Extreme skewing of X-chromosome inactivation is observed in
female carriers of the ATR-X syndrome due to a negative selection
of those cells with the active mutant allele [Lossi et al., 1999].
Similarly, all the Xq13q21 duplication-carrier women so far tested,
as the mother of Patient 2, showed a complete inactivation of the
abnormal X chromosome. Although this is not a rare event in X-
chromosome rearrangements, it gives further support to the im-
plication of ATRX as the main candidate gene within the common
duplicated region.
ACKNOWLEDGMENTS
This study was supported by grants PI11/00389 (ISCIII -Subdir-
ección General de Evaluación y Fomento de la Investigación, PN de
I þ D þ I 2008–2011), FEDER (Fondo Europeo de Desarrollo
Regional, EU), and Fundación Ramón Areces.
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