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Different-sized duplications of Xq28 including MECP2 in three males with mental retardation absent or delayed speech and recurrent infections.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:799 –806 (2008)
Different-Sized Duplications of Xq28, Including MECP2, in
Three Males With Mental Retardation, Absent or Delayed
Speech, and Recurrent Infections
M. Smyk,1 E. Obersztyn,1 B. Nowakowska,1,2 M. Nawara,1 S.W. Cheung,2 T. Mazurczak,1
P. Stankiewicz,1,2 and E. Bocian1*
1
Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
2
In XY males, duplication of any part of the X
chromosome except the pseudoautosomal region
leads to functional disomy of the corresponding
genes. We describe three unrelated male patients
with mental retardation (MR), absent or delayed
speech, and recurrent infections. Using highresolution comparative genomic hybridization
(HR-CGH), whole genome array comparative
genomic hybridization (array CGH), fluorescent
in situ hybridization (FISH), and multiplex ligation probe amplification (MLPA), we have identified and characterized two different unbalanced
Xq27.3-qter translocations on the Y chromosome
(approx. 9 and 12 Mb in size) and one submicroscopic interstitial duplication (approx. 0.3–1.3 Mb)
involving the MECP2 gene. Despite the differences in size of the duplicated segments, the
patients share a clinical phenotype that overlaps
with the features described in patients with
MECP2 duplication. Our data confirm previous
observations that MECP2 is the most important
dosage-sensitive gene responsible for neurologic
development in patients with duplications on the
distal part of chromosome Xq. ß 2007 Wiley-Liss, Inc.
KEY WORDS:
array CGH; HR-CGH; gene dosage;
psychomotor retardation; absent
speech
Please cite this article as follows: Smyk M, Obersztyn E,
Nowakowska B, Nawara M, Cheung SW, Mazurczak T,
Stankiewicz P, Bocian E. 2008. Different-Sized Duplications of Xq28, Including MECP2, in Three Males With
Mental Retardation, Absent or Delayed Speech, and
Recurrent Infections. Am J Med Genet Part B 147B:799–
806.
of the corresponding genes, whereas females with Xq duplications are usually phenotypically normal [Schmidt et al., 1991;
Sanlaville et al., 2005]. Duplications involving the distal region
of the long arm of X chromosome are rare. To date, at least
19 males and females with terminal Xq duplications have been
described [Lachlan et al., 2004; Novelli et al., 2004; Sanlaville
et al., 2005]. These patients shared clinical symptoms of
prenatal growth retardation, severe mental retardation (MR)/
developmental delay, hypotonia, hypoplastic genitalia, and/or
cryptorchidism, severe feeding difficulties, recurrent infections, microcephaly, small and open mouth, ear anomalies,
abnormal fingers and toes, and absence of or severely retarded
speech [Vasquez et al., 1995; Goodman et al., 1998; Akiyama
et al., 2001; Lachlan et al., 2004; Novelli et al., 2004; Sanlaville
et al., 2005]. Interestingly, in some neonatal cases, a resemblance to Prader–Willi syndrome has been noted [Goodman
et al., 1998; Gecz et al., 1999; Lammer et al., 2001; Lachlan
et al., 2004; Sanlaville et al., 2005]. Recently, due to application of array comparative genomic hybridization (array CGH)
and real-time quantitative PCR, one female and 45 male
patients from 20 families with submicroscopic interstitial
duplication, and one male patient with triplication involving
Xq28 have been reported. The region of duplication ranged in
size from 0.2 to 2.2 Mb and included the MECP2 gene [Ariani
et al., 2004; Meins et al., 2005; Van Esch et al., 2005; del Gaudio
et al., 2006; Friez et al., 2006; Lugtenberg et al., 2006]. The
patients manifested some clinical features overlapping with
characteristics described in patients with larger duplications
of terminal Xq [Van Esch et al., 2005; del Gaudio et al., 2006].
We describe three unrelated males with MR, absent or
delayed speech, and recurrent infections due to the Xq
duplications involving MECP2. A detailed clinical evaluation
and comparison with similar cases from the literature is
presented.
CLINICAL REPORT
Patient 1 (MT)
INTRODUCTION
Duplications of any part of the X chromosome except the
pseudoautosomal region in XY males lead to functional disomy
Grant sponsor: Polish Ministry of Scientific Research and
Information Technology; Grant numbers: 2P05A 191-29,
40101731/0307, PBZ/KBN 122/P05/2004/01-9, 2P05A 128 28.
*Correspondence to: Prof. E. Bocian, Ph.D., Department of
Medical Genetics, Institute of Mother and Child, Kasprzaka 17A,
01-211 Warsaw, Poland. E-mail: ebocian@imid.med.pl
Received 4 May 2007; Accepted 30 October 2007
DOI 10.1002/ajmg.b.30683
ß 2007 Wiley-Liss, Inc.
The proband was an 8-year-old boy, first son of healthy
and non-consanguineous parents (a 19-year-old mother and a
25-year-old father). Family history was negative for MR and
congenital malformations but the proband’s mother had three
early miscarriages. The pregnancy was uneventful until
32 weeks when a maternal urinary tract infection was
diagnosed. Cesarean section was performed at 37 weeks
because of fetal distress due to maternal health problems:
proteinuria, edema of the limbs and high blood pressure. Birth
weight was 1750 g (<5th centile), length 45 cm (5th centile),
and occipitofrontal circumference (OFC) 29 cm (<5th centile).
Apgar scores were 5 and 10 at 1 and 5 min, respectively. At
birth, bilateral cryptorchidism was noted. The child had
congenital pneumonia and meconium ileus was suspected at
this time. Persistent hyperbilirubinemia and secondary metabolic acidosis were observed during his first 2 weeks of life.
800
Smyk et al.
Because of recurrent respiratory tract infections and failure to
thrive, cystic fibrosis was considered but was excluded at
6 months. Global muscular hypotonia and significantly
delayed psychomotor development were noticed from birth.
At the age of 8 years, he could sit unsupported but could not
stand up. The speech was limited to several unintelligible
sounds. CT of brain showed global dilatation of the subarachnoid space, a septum pellucidum cyst and delayed myelination of the white cortex. Anthropometric evaluation showed
short stature (<5th centile), microcephaly (OFC <5th centile),
and obesity with BMI >97th centile. The following dysmorphic
features were noted: small bifrontal diameter, frontal bossing,
flat occiput, round and expression-less face, open mouth, large
tongue, relatively large, low-set and prominent ears, short
nose, bristly hair, short neck with low posterior hairline,
camptodactyly, and tapering fingers (Fig. 1a). Axial hypotonia
and spasticity of upper and lower limbs were also observed. At
the age of 9 years, he developed recurrent tonic-clonic seizures
and epilepsy was diagnosed. He died at the age of 11 years
because of respiratory insufficiency during a viral infection and
status epilepticus.
Patient 2 (AS)
The proband is a male infant, the second child of healthy
and non-consanguineous parents (a 33-year-old mother and a
43-year-old father). His older sibling is healthy. Family history
was negative for MR, congenital malformations or exposure to
known teratogens. The child was born at 38 weeks gestation
after an uneventful pregnancy. The Apgar scores were 8 and 10
at 1 and 5 min, respectively. He showed clinical symptoms of
congenital infection and intrauterine growth retardation.
His birth weight was 2350 g (<5th centile), length 49 cm
(<50th centile), and OFC 31 cm (<5th centile). Feeding
difficulties with poor sucking and muscle hypotonia were
observed during neonatal period. Brain MRI performed at
3 months showed agenesis of the corpus callosum, severe delay
of white cortex myelination and ventricular dilatation. Additionally, gastroesophageal reflux was detected. In the differential diagnosis of unexplained hypotonia, the Prader–Willi/
Angelman syndromes were excluded. Clinical assessment in
the Genetic Counseling Unit was performed at 18 months. He
demonstrated severe psychomotor retardation with absent
speech, axial hypotonia, microcephaly, and bilateral cryp-
Fig. 1.
torchidism. He was unable to sit or change body position. Brisk
tendon reflexes and subtle spasticity were noted in the
neurological examination. Recurrent respiratory infections
were also reported. Facial dysmorphism with asymmetrical
cranium, flat occiput, prominent forehead, round face, full
cheeks, open mouth, down-slanting palpebral fissures, epicanthic folds, broad nasal root, short nose, relatively large ears
with thickened helix, short neck, and increased subcutaneous
skin folds were described. There were no seizures or other
neurological symptoms.
Patient 3 (TG)
The proband, a 3-year-old boy from the second pregnancy
of healthy and non-consanguineous parents (a 27-year-old
mother and a 28-year-old father), was evaluated because of
features of psychomotor retardation. His older sibling is
healthy. The proband was born after uneventful pregnancy
at the gestational age of 40 weeks. The Apgar scores were 10 at
1 and 5 min. His birth weight was 4100 g (>90th centile), length
50 cm (>50th centile), and OFC 35 cm (50th centile). Bilateral
cryptorchidism was revealed after birth. The neonatal period
was uncomplicated. Psychomotor retardation was observed since infancy; he walked at the age of 19 months and could
speak only few words at the age of 2 years. Storage diseases,
especially mucopolysaccharidosis, were suspected at this time
because of the facial dysmorphism, but were excluded after
obtaining the results of the lysosomal enzymes investigations.
No mutation was found in the FMR1 gene. A detailed clinical
assessment in the Genetic Counseling Unit was performed at
age 17 years. Anthropometric investigation showed proportional body weight, length, and OFC; all parameters were
within normal range. Psychological evaluation showed moderate MR with a pleasant personality. IQ was below 50 (in
Wechsler’s scale). He could speak only about 20 simple words of
one or two syllables. The speech was mumbling. His gait was
unsteady with slightly bent knees. Progressive spasticity has
been observed from puberty. Seizures have not been noted.
However, an abnormal electroencephalography registration
was documented.
Dysmorphic features with long face (despite round face in
early childhood), full lips, open mouth, synophrys, large and
prominent simple ears, prognathism, dental caries, and
macroorchidism were noted (Fig. 1b). The sister of the
Patient 1 (a) and Patient 3 (b). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
Functional Disomy and Trisomy of Xq28 in Males
proband’s mother has two mentally retarded sons with
reportedly similar features. Unfortunately, they were unavailable for further clinical evaluation and investigations. One of
them could speak only few simple words of one or two syllables
and both had dysmorphic facial features with expression-less
face, open mouth, synophrys, large prominent ears, and large
testes. Both had epilepsy and one of them demonstrated
symptoms of infantile cerebral palsy with spasticity and brisk
tendon reflexes.
METHODS
Cytogenetic and FISH Studies
Conventional karyotyping using GTG, CBG-banding, and
fluorescent in situ hybridization (FISH) with BAC clones was
performed on PHA-stimulated peripheral blood lymphocytes
using standard protocols [Shaffer et al., 1997]. BAC clones
were identified from the existing physical maps (UCSC genome
browser, http://genome.ucsc.edu).
801
RESULTS
Patient 1 (MT)
GTG-banding revealed a 46,X,der(Y) karyotype with additional material on the short arm (Fig. 2a). Cytogenetic analysis
of the patient’s parents showed the rearrangement to be a de
novo event. HR-CGH analysis demonstrated that it originated
from the Xq27.2-qter region (Fig. 2b). The translocation t(X;Y)
was confirmed by FISH with the wcpX probe (Fig. 2c). FISH
analysis with X chromosome-specific BAC clones mapped the X
chromosome breakpoint to q27.3 between two adjacent BAC
clones RP11-433F22 and RP11-1091C11 (Table I). The size of
the duplication was estimated as 12 Mb. The breakpoint
on chromosome Y was mapped to Yp11.32, between the BAC
clones RP11-257O13 and RP11-309M23, identifying a 1–
1.2 Mb deletion involving the SHOX gene. The patient’s
karyotype was designated as 46,X,add(Y).ish der(Y)t(X;Y)
(q27.3;p11.32)(wcpXþ,RP11-479B17þ,RP11-1091C11þ,RP11433F22,RP11-309M23,RP11-257O13þ).
Patient 2 (AS)
HR-CGH and Array CGH
The probands’ genomic DNAs were isolated from the peripheral blood. HR-CGH was performed as previously described
[Kirchhoff et al., 2000]. Array-CGH designed to cover genomic
regions of 75 known genomic disorders including Rett
syndrome region, all 41 subtelomeric regions, and 43 pericentromeric regions (Baylor College of Medicine, Chromosome
Microarray Analysis, V.5, http://www.bcm.edu/cma/assets/
abnormalities.pdf) was used as previously described [Cheung
et al., 2005].
XCI Status
X-inactivation study was performed by using the androgen
receptor gene methylation assay described by Allen et al.
[1992].
Multiplex Ligation-Dependent Probe Amplification
Copy-number analysis of the MECP2 gene and the flanking
regions was performed by multiplex ligation-dependent probe
amplification (MLPA) (MRC-Holland, Amsterdam, Netherlands). The reactions were performed on GeneAmp PCR
System 9700 (Applied Biosystems, Foster City, CA) according
to manufacturer’s instructions. Products were separated
on ABI 3730 DNA Analyser and the data were analyzed for
copy-number differences with the Gene Marker software
(Softgenetics, State College, PA).
Standard chromosome analysis revealed a 47,XX,der(Y)
karyotype with a small submetacentric Y chromosome
(Fig. 3a). CBG-banding showed the heterochromatic region
on Yq was deleted. The results of cytogenetic analyses of the
parents were normal. FISH with DYZ3 and wcpY probes
confirmed that the derivative chromosome originated from the
Y chromosome and revealed that it had additional material on
the long arm. HR-CGH analysis showed a duplication of the
Xq27.3qter region (Fig. 3b). The origin of the additional
material on Yq was confirmed by FISH with the wcpX probe.
The breakpoint on chromosome X was mapped between two
adjacent BAC clones RP11-522P6 and RP11-226B15 (Fig. 3c) in
a subband q27.3 (Table I). The fluorescent signal for RP11226B15 present on chromosome Y was faint, indicating that
the breakpoint maps within this clone. Xq translocated fragment was estimated as 9 Mb in size harboring L1CAM,
IRAK1, and MECP2. The breakpoint on chromosome Yq was
mapped within the sub-sub-subband Yq11.223, between the
BAC clones RP11-106G5 and RP11-539D10, demonstrating a
deletion of the AZFc region with the DAZ3 gene (Fig. 3c). The
patient’s karyotype was designated as 47,XX,þder(Y).ish der(Y)
t(X;Y)(q27.3;q11.223)(wcpYþ,RP11-106G5þ,RP11-539D10,
RP11-522P6,RP11-226B15þ, RP11-479B17þ, DYZ3þ).
Patient 3 (TG)
GTG-banding chromosome analysis on the proband’s blood
lymphocytes showed a normal male karyotype. Examination of
Fig. 2. The results of investigation in Patient 1. (a) Chromosomes X and der(Y) after GTG-banding. Note the additional material on the short arm of
chromosome Y. (b) HR-CGH profile showing a duplication of the Xq27.2-q28 region. (c) The result of FISH with the wcpX probe. [Color figure can be viewed in
the online issue, which is available at www.interscience.wiley.com.]
802
Smyk et al.
TABLE I. Summary of the Array CGH and FISH Results
Location
XLMR genes (distance
from Xpter in Mb)
Xq27.1
Xq27.2
Xq27.3
FMR1 (146.8)
FMR2 (147.8)
IDS (148.3)
Xq28
ABCD1 (152.6) SLC6A8 (152.6)
L1CAM (152.7)
MECP2 (152.9)
FLNA (153.2) GDI1 (153.3)
IKBKG (153.4) DKC1 (153.6)
Clone
Patient 1
Patient 2
Distance
from Xpter
(Mb)
FISH
signal
FISH
signal
Array CGH
combined (log 2 ratio)
FISH
signal
139.0
141.1
141.9
142.7
142.9
143.0
143.5
143.9
144.2
144.7
144.9
145.3
145.6
145.7
145.8
146.0
146.2
146.4
146.8
147.7
148.8
148.9
148.9
152.5
152.8
153
153
154
154.4
154.7
1x
1x
1x
1x
1x
2x
2x
2x
2x
2x
2x
2x
2x
2x
2x
2x
2x
2x
2x
2x
2x
2x
2x
n/a
n/a
n/a
n/a
n/a
n/a
2x
n/a
n/a
n/a
n/a
n/a
2x
2x
2x
2x
2x
2x
2x
2x
2x
2x
3x
3x
3x
3x
3x
3x
3x
3x
n/a
n/a
n/a
n/a
n/a
n/a
3x
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
0.039
0.483
0.371
0.379
n/a
0.045
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
2x
n/a
2x
1x
n/a
n/a
RP11-147G11
RP11-435F11
RP11-179F2
RP11-513H18
RP11-433F22
RP11-1091C11
RP11-99J24
RP11-1145K2
RP11-466E7
RP11-269F10
RP11-387H19
RP11-183K14
RP11-243C2
RP11-691H16
RP11-522P6
RP11-226B15
RP11-42J13
RP11-25E18
RP11-489K19
RP11-62J13
RP11-49C9
RP11-722C13
RP11-716M16
RP11-54I20
RP11-244I10
RP11-119A22
RP4-671D9
RP11-810M4
RP11-218L14
RP11-479B17
Patient 3
Highlighted in bold are results for the clones in excess copy-number.
the proband’s DNA using array CGH revealed a duplication of
two BAC clones: RP11-244I10, RP11-119A22, and one PAC
clone RP4-671D9 (Fig. 4a), involving the entire MECP2 gene.
FISH analysis confirmed the duplication. The proximal breakpoint of the duplication was mapped between BAC clones
RP11-54I20 and RP11-244I10 and the distal breakpoint
between clones RP4-671D9 and RP11-810M4 (Table I). The
size of the duplication was estimated as approximately 0.3–
1.3 Mb. FISH examination of the maternal peripheral blood
lymphocytes showed that the mother was a carrier of the
duplication (Fig. 4b). Analysis of XCI status in the asympto-
matic carrier mother showed an extremely non-random
pattern with a ratio of 99:1. The karyotype of the patient was
designated as 46,XY.arr cgh Xq28(RP11-244I10,RP4-671D9,
RP11-119A22) 2
nuc ish dup(X)(q28q28)(RP11-244I10,RP4-671D9) 2 mat.
The presence of the microduplication was confirmed also by
MLPA (Fig. 4c). In addition to MECP2, the duplication also
includes the IRAK1 and L1CAM genes (11 Kb and 160 Kb
upstream to MECP2, respectively), and does not contain
IDH3G, SLC6A8 (236 Kb and 507 Kb upstream to MECP2,
respectively), or SYBL1 (1754 Kb downstream) (Fig. 4c).
Fig. 3. The results of investigation in Patient 2. (a) Chromosomes X and der(Y) after GTG-banding. Note the additional material on the long arm of
chromosome Y. (b) HR-CGH profile showing a duplication on the Xq27.3q28 region. (c) Metaphase chromosomes after FISH with clones RP11-226B15 (red)
and RP11-470K20 (green); note that third red signal present on chromosome Y is faint, indicating that the breakpoint maps within RP11-226B15. [Color
figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
Functional Disomy and Trisomy of Xq28 in Males
803
Fig. 4. The results of investigation in Patient 3. (a) The result of array CGH. This combined profile represents two hybridizations performed
simultaneously with dye reversal using reference DNA. There are three clones RP11-244I10, RP11-119A22, RP4-671D9 from Xq28 that showed
displacement, indicating a gain of Xq material in the patient versus the reference DNA. (b) Interphase nucleus after FISH with RP4-671D9 (red) and RP11810M4 (green) showed that the mother of the proband is the carrier of the duplication. (c) MLPA raw data of a patient with the duplication (blue peaks)
compared with a normal control (red peaks). The amount of PCR product for all MECP2 exons and IRAK1 and L1CAM genes is higher for probes located in the
duplicated region. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
DISCUSSION
Functional disomies involving chromosome Xq in males are
rare and can lead to abnormal phenotype caused by either
disruption of a gene at the breakpoint or by the increased
dosage of a gene within the duplicated segment. The chromosome region Xq27.3-qter harbors several genes that have been
shown to be responsible for syndromic and non-syndromic
forms of X-linked MR (XLMR) (e.g., FMR1, IDS, ABCD1,
L1CAM, MECP2, FLNA, IKBKG, and DKC1; and FMR2,
GDI1, SLC6A8, and MECP2, respectively) [Ropers, 2006].
We report three unrelated male patients with abnormal
phenotypes resulting from duplications of distal Xq. The Xq
duplicated segments in our patients vary in size; however, in
all three cases they encompass the L1CAM and MECP2 genes.
Mutations in MECP2 give rise to a wide range of disorders
including Rett syndrome (MIM 312750) [Amir et al., 1999;
Williamson and Christodoulou, 2006], a progressive neurologic
developmental disorder and one of the most common causes of
MR in females; severe encephalopathy [Villard et al., 2000];
PPM-X syndrome (MR with psychosis, pyramidal signs, and
macroorchidism) [Klauck et al., 2002]; progressive spasticity
[Meloni et al., 2000]; non-syndromic XLMR [Orrico et al.,
2000], and Angelman syndrome-like [Watson et al., 2001],
and Prader–Willi syndrome-like phenotypes [Kleefstra et al.,
2002].
Recently, 20 families with cryptic duplication and one case
with submicroscopic triplication involving MECP2 have been
reported [Ariani et al., 2004; Meins et al., 2005; Van Esch et al.,
2005; Friez et al., 2006; Lugtenberg et al., 2006; del Gaudio
et al., 2006]. In all cases, the duplicated segment ranged in size
between 0.2 and 2.2 Mb. The common phenotypic features in
these patients included infantile hypotonia, severe to profound
MR, absence of speech development, recurrent infections,
seizures, and progressive spasticity [Van Esch et al., 2005;
Friez et al., 2006; Lugtenberg et al., 2006]. However, no typical
facial dysmorphic features could be assigned to MECP2
duplication. Furthermore, no correlation between the size of
the duplication and severity of the phenotype was noted;
however, the patient with the triplicated MECP2 gene had the
most severe phenotype [del Gaudio et al., 2006]. Except one
case, female carriers of duplication were asymptomatic, like
the mother of Patient 3 [Friez et al., 2006; del Gaudio et al.,
2006]. The phenotypes observed in our patients as well as in
two severely affected male cousins of Patient 3 overlap with
most of the clinical features reported in patients with MECP2
duplication (Table II) [Van Esch et al., 2005; Friez et al., 2006;
Lugtenberg et al., 2006]. In contrast to other MECP2
duplication cases, our Patient 3 had large testes that are also
found in patients with the PPM-X syndrome; however, up to
now no psychotic symptoms have been observed [Klauck et al.,
2002]. Moreover, axial hypotonia, commonly found in patients
with MECP2 duplication, was also present in Patients 1 and 2.
The motor development was significantly delayed in all
patients, especially in Patient 1 who has never walked. In
addition, both progressive spasticity and epilepsy were present
in Patient 1. However, no epilepsy and only subtle spasticity
have been observed in Patient 2 (likely due to his young age).
804
Smyk et al.
TABLE II. Comparison of Clinical Symptoms Observed in Our Patients and Previously Reported Cases With Different Sized
Duplications of Xq Encompassing MECP2
Clinical features
Developmental delay
Hypotonia
Growth retardation
Absent or delayed speech
Never walked or limited
walking
Spasticity
Severe feeding difficulties
Gastrointestinal reflux
Recurrent infections
Seizures
Obesity
Microcephaly
Brachycephaly
Asymmetric skull
Facial hypotonia
(expressionless face)
Epicanthal folds
Large ears
Small/open mouth
Digital abnormalities
Genital abnormalities:
including Hs, Cr, LT
Duplications
Xq27qterb
Duplications
Xq28qterc
Interstitial duplications
including MECP2
0.2–2.2 Mb in sized
Pt 1
Pt 2
Pt 3
Duplications
Xq26.3qtera
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
4/4
4/4
4/4
n.r.
n.r.
8/8
8/8
8/8
5/7
5/7
5/5
5/5
3/5
4/5
5/5
43/43
26/29
1/1
39/40
20/33
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
n.r.
2/4
n.r.
4/4
1/4
n.r.
4/4
n.r.
n.r.
n.r.
n.r.
4/6
1/3
7/9
1/7
n.r.
8/8
n.r.
n.r.
1/2
1/2
2/2
1/2
2/2
3/3
n.r.
5/5
n.r.
n.r.
n.r.
16/20
15/28
13/16
32/39
22/41
n.r.
5/39
5/7
2/12
18/27
þ
þ
þ
Cr
þ
þ
þ
Cr
þ
þ
Cr, LT
n.r.
1/3
3/3
3/4
4/4
4/5
4/5
3/3
5/8
6/8
n.r.
2/2
3/5
4/5
3/5
1/7
3/19
4/18
6/19
3/8
Hs, hypospadias; Cr, cryptorchidism; LT, large testes; n.r., not reported.
a
Akiyama et al. (2001); Vasquez et al. (1995); Kokalj-Vokac et al. (2004).
b
Goodman et al. (1998); Lammer et al. (2001); Lachlan et al. (2004); Novelli et al. (2004).
c
Lahn et al. (1994); Sanlaville et al. (2005).
d
Ariani et al. (2004); Meins et al. (2005); Van Esch et al. (2005); Friez et al. (2006); del Gaudio et al. (2006).
Patient 3 has not manifested epilepsy; however, brain
encephalography registration was abnormal. Interestingly,
both Patients 1 and 2 had delayed brain myelination that was
also observed in some of the previous patients with Xq
duplications [Sanlaville et al., 2005; Van Esch et al., 2005].
Mutations in L1CAM, another gene located in the duplicated
Xq region cause X-linked spastic paraplegia (MIM 312900),
MASA syndrome (MIM 303350), and X-linked hydrocephalus
due to stenosis of the aqueduct of Sylvius (HSAS; MIM 307000)
(Jouet et al., 1994; Vits et al., 1994]. L1CAM has been proposed
to be a dosage-sensitive gene that contributes to the MECP2
duplication phenotype; however, recently, two patients with
duplications involving MECP2 but not L1CAM had the typical
MECP2 duplication phenotype, thus likely disproving this
hypothesis [Meins et al., 2004; Friez et al., 2006].
The recurrent infections in patients with Xq duplications
have been stressed by many authors. This may result from
the increased dosage of the IRAK1 or IKBKG genes contained
in the duplicated region. IKBKG encodes the NF-kappa-B
essential modulator (NEMO) protein which is a master
regulator of proinflammatory responses [Nenci et al., 2007].
Mutations in IKBKG result in immunodeficiency. However,
there are no reports on the causative role of duplication of the
entire IKBKG gene. Moreover, recurrent infections have been
also reported in patients that did not have increased dosage
of IKBKG [Van Esch et al., 2005; del Gaudio et al., 2006].
The second candidate gene, IRAK1, is duplicated in all of the
hitherto reported cases. IRAK1 encodes interleukin-1 receptor-associated kinase, also involved in proinflammatory
cytokine response. This gene is partially responsible for IL1induced upregulation of the transcription factor NF-kappa-B.
Interestingly, increased transcript level of Irak1 was reported
in a mutant MeCP2-deficient mouse [Jordan et al., 2007]. In
addition to MECP2, L1CAM, and IRAK1, the minimal
common duplicated Xq region also contains AVPR2, ARHGAP4, ARD1A, RENBP, HCFC1, and TMEM187 genes.
Recently, a patient with severe combined immunodeficiency
and X-linked nephrogenic diabetes insipidus (NDI) carrying
a microdeletion including AVPR2, ARHGAP4, and ARD1A
has been described [Broides et al., 2006]. The highly
conserved intragenic region between ARHGAP4 and ARD1A
was not deleted in other patients with NDI but without
immunodeficiency.
To date, at least 19 patients with larger-sized duplications
involving Xqter have been described [Lahn et al., 1994;
Vasquez et al., 1995; Goodman et al., 1998; Lachlan et al.,
2004; Novelli et al., 2004; Sanlaville et al., 2005]. In addition to
clinical features described in patients with MECP2 duplication, microcephaly, growth retardation, abnormal palate/
maxillar alveolus, facial dysmorphism with a wide face,
pointed nose and small mouth, feeding problems, and abnormal genitalia have been reported [Sanlaville et al., 2005]. Both
our Patients 1 and 2 also presented with microcephaly, growth
retardation, small mouth, cryptorchidism, and severe feeding
problems in neonatal period.
The duplicated segments in Patients 1 and 2 are, respectively, 12 and 9 Mb in size, and in addition to MECP2,
harbor also the GDI1 gene, known to be responsible for
the nonsyndromic XLMR [D’Adamo et al., 1998]. Recently, a
duplication encompassing the GDI1, FLNA, and EMD genes
has been reported in a family with three affected male patients
with moderate MR, peculiar facial dysmorphism, and microcephaly and two asymptomatic female carriers [Madrigal et al.,
2007]. Interestingly, in all male patients carrying the duplication, a significantly increased level of GDI1 mRNA was noted.
Mutations in the FLNA gene cause bilateral periventricular
nodular heterotopia (BPNH). This feature was also reported
in a boy carrying a 2.25–3.25 Mb inverted duplication
Functional Disomy and Trisomy of Xq28 in Males
encompassing FLNA [Fink et al., 1997]. However, Lugtenberg
et al. [2006] reported duplications involving the GDI1 and
FLNA genes in phenotypically normal males, suggesting that
these are most likely nonpathogenic copy-number variations
(CNVs). Supporting this notion, Patients 1 and 2 with duplication encompassing FLNA do not have BPNH, indicating that
this feature may not be associated with the increased dosage of
this gene.
Patient 1 has also a 1 to 1.2 Mb deletion in Yp11.32,
involving the pseudoautosomal homeobox SHOX gene.
Haploinsufficiency of SHOX causes short stature and skeletal
features in Turner syndrome [Rao et al., 1997] and Leri–Weill
dyschondrosteosis (LWD; MIM 127300) [Belin et al., 1998].
This patient does not have any skeletal deformities typical for
LWD; however, he has a short stature below 5th centile.
Interestingly, the obesity present in Patient 1 was reported
in one patient with an interstitial duplication involving
Xq27.1q28 [Lachlan et al., 2004] but in none of the cases with
terminal duplication.
Patient 2 has a deletion on the Y chromosome encompassing
the AZFc region with the DAZ3 gene. Deletions removing
DAZ3/DAZ4 may have some effects on fertility [Ferlin et al.,
2005]. However, this patient will most likely be infertile due to
an abnormal sex chromosome complement, XXY.
In summary, the increased dosage of MECP2 in our patients
is likely responsible for most of their features including severe
MR, hypotonia, absent or delayed speech, epilepsy, and
spasticity. Recurrent infections can be caused by duplication
of IRAK1. Other common abnormalities described in Patients 1
and 2 including microcephaly, growth retardation, facial
dysmorphism with a round face and full cheeks in neonatal
period, short nose, small mouth, large and prominent simple
ears, and feeding problems are not specific for MECP2 and may
result from increased dosage of other genes mapping in the
duplicated regions. Our data indicate that in each case of MR in
males, a possibility of duplication Xq28 has to be considered,
especially when hypotonia, absent/delayed speech, and recurrent infections are observed.
ACKNOWLEDGMENTS
We thank Sandra Peacock for helpful discussion. Supported
in part by grants from the Polish Ministry of Scientific
Research and Information Technology Grants 2P05A 191-29,
40101731/0307, PBZ/KBN 122/P05/2004/01-9, and 2P05A 128
28.
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