CONGENITAL HYDROCEPHALUS AND HEMIVERTEBRAE
ASSOCIATED WITH DE NOVO PARTIAL MONOSOMY
6q (6q25.3→qter)
Li Y, Choy K-W, Xie H-N, Chen M, He W-Y, Gong Y-F,
Liu H-Y, Song Y-Q, Xian Y-X, Sun X-F, Chen X-J,
*Corresponding Author: Xin-Jie Chen, Ph.D., Key Laboratory of Reproductive Medicine of Guangdong Province,
Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and
Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University,
Duobao Road 63, Guangzhou, 510150, Guangdong, People’s Republic of China. Tel: +86-20-81292292.
Fax: +86-20-81292013. E-mail: lucychen23@aliyun.com
page: 77
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DISCUSSION
Hemivertebrae is a rare congenital spinal malformation
in which only one side of the vertebral
body develops, leading to a secondary deformation
of the spine, such as scoliosis or kyphosis [7,10]. The
condition is found in five to ten per 10,000 births, occurring
more commonly in girls [9]. Hemivertebrae
may exist alone, but more commonly, hemivertebrae
occur with multiple congenital abnormalities, such
as skeletal anomalies of the spine, ribs, and limbs;
diastematomyelia; cardiac system and genitourinary
tract anomalies; and central nervous system (CNS),
deformities, either in prenatally or postnatally diagnosed
cases [6-10]. Notably, hemivertebrae may
be involved in several genetic syndromes, including
Jarcho-Levin syndrome, Klippel-Feil syndrome
and VATER syndrome (vertebral anomalies, imperforate
anus, tracheoesophageal fistula, and renal
anomalies) [6,12]. The etiology of hemivertebrae
is not clear because it usually occurs sporadically;
thus the likelihood of genetic involvement has been
considered low. Several chromosome deletions associated
with hemivertebrae have previously been
reported in earlier studies. These deletions include
del(1q4), del(3p2), monosomy 4p, interstitial 5qdeletion,
r(15) and interstitial deletion of 17p [13].
However, more recent studies have shown that the
correlation between hemivertebra and chromosomal
abnormalities is small. Fetal karyotypes are usually
normal whether the hemivertebrae are isolated or non
isolated, although non isolated hemivertebrae may
be associated with an increased risk of aneuploidy
[7,12]. Therefore, the complexity and uncertainty of
the cause of hemivertebrae contribute to the difficulty
of interpreting the genotype-phenotype correlations
in our case.
With regard to hemivertebrae associated with 6q
terminal deletion, hemivertebrae generally emerges
as a deformity accompanying major anomalies associated
with 6q subtelomeric deletions. Nevertheless,
the 6q terminal region has never been considered
as a candidate chromosomal region that could be
responsible for hemivertebrae, and the underlying
genotype-phenotype correlations require further investigation.
The T (also known as Brachyury) gene
that maps to 6q27 encodes a transcription factor that
is essential for normal mesodermal development and
the formation and differentiation of the notochord in
all vertebrates. The notochord controls cell migration
and differentiation in those tissues that are most often
involved in sacral agenesis, the neural tube, and the
sclerotomal cells that form the vertebrae. In mice, mutations of the T gene lead to the lack of expression
of the product and have been recognized as the
cause of dominant Brachyury and death in utero,
with an abnormal notochord and absent somites. The
T gene has been proposed as a candidate gene for
sacral agenesis in humans. Furthermore, a previous
study of congenital vertebral malformations (CVMs)
indicated that missense mutations in the T gene might
result in the pathogenesis of human CVMs as one of
the genetic components [14]. The CVMs are a class of
disorders composed of hemivertebrae, vertebral bars,
supernumerary vertebrae, and butterfly- and wedgeshaped
vertebrae. Although there is no evidence addressing
the direct correlation between the T gene
and hemivertebrae, taken together, it is possible that
copy number loss resulting from haploinsufficiency
of this gene might have substantially contributed to
the hemivertebrae malformation observed in our case.
Congenital hydrocephalus can occur as an isolated
abnormality or in combination with many genetic
syndromes, referred to as multiple congenital anomalies
(MCAs), in various body systems [15,16]. The
main clinical sign in most fetuses with congenital hydrocephalus
is cerebral ventriculomegaly [16], which
is a pathological dilatation of the cerebral ventricular
system and might be a consequence of obstruction of
the flow of cerebral spinal fluid (CSF), hyper-secretion,
defective filtration or a developmental anomaly
of the intracranial architecture [5].
To date, the specific causes of congenital hydrocephalus
in the majority of cases remain under
investigation. Garne et al. [17] recently demonstrated
that 87 fetuses and infants with congenital hydrocephalus
exhibited a low rate of karyotype anomalies
(9.0%). However, evidence from previous studies
suggests that the genetic etiology probably plays
an important role in congenital hydrocephalus. Indeed,
approximately 40.0% of cases of congenital
hydrocephalus may be attributable to genetic factors,
including cytogenetic abnormalities, monogenic or
complicated inherited conditions and multifactorial
disorders [17], although non syndromic hydrocephalus
appears to be less related to these conditions.
Based on the literature, except for the most common
cytogenetic abnormalities such as aneuploid and
multiploid karyotypes, submicroscopic chromosomal
aberrations, also known as genomic CNVs, represent
an important genetic cause in a growing number of
cases. The variant regions in most chromosomes have
been previously described. In particular, 6p terminal
deletions have been rather frequently reported to be
associated with congenital hydrocephalus. However,
most previous reports were based on syndromic hydrocephalus
(≥1 major and >2 minor anomalies), and
non syndromic (no major and ≤2 minor anomalies)
cases have rarely been described. In addition, few
studies have elucidated the molecular basis of the
disease phenotype or the relationship between the
CNVs and phenotypic characteristics. In the present
study, the proband exhibited features that are known
to be associated with the terminal 6q deletion phenotype.
This fetus presented bilateral hydrocephalus/
ventriculomegaly and a lumbar hemivertebrae but
lacked the typical phenotypic features of subtelomeric
6q deletion, such as developmental delay, corpus
callosum anomalies, microcephaly, cleft palate and
hyperactivity [2,3,5], which was considered unusual
for such a large deletion, spanning 10.04 Mb. Until
now, very few cases of prenatal ventriculomegaly due
to submicroscopic terminal 6q deletions have been
reported, and in those cases, the extent of the deletion
with respect to non syndromic ventriculomegaly was
less than 5 Mb [5,18]. For postnatal cases, Lee et al.
[3] made a comprehensive summary of 28 patients
diagnosed postnatally with subtelomeric 6q deletions
of ≤11 Mb and idiopathic intellectual disability,
developmental delay and/ or dysmorphic features.
These authors reported that smaller 6q terminal deletions
tended to cause milder anomalies. Accordingly,
we speculated that the size of the deletion appears
to be correlated with the clinical complexity of the
phenotype. Thus, the fetus in our study should have
more severe malformations and more types of abnormalities
because the deleted region held more
functional genes that could contribute to the clinical
manifestation. However, it is more likely that several
specific genes located within the deleted segment play
a role in the genesis of hydrocephalus.
The TBP gene is most frequently mentioned
in relation to the 6q terminal deletion phenotype
[3,5,18-20]. This gene encodes a TATA-binding protein,
which is a subunit of the RNA polymerase II
transcription factor that affects the initiation of transcription.
It has been found to be highly expressed in
the cerebral cortex, the frontal, parietal and occipital
lobes and the caudate nucleus, and it has an important
role in CNS morphogenesis [19,20]. Deletion of TBP
may affect the elaboration of cortical neurons, and cortical maldevelopment could contribute to mental
retardation and seizures, which are commonly seen
in patients with 6q terminal deletions [20]. Moreover,
dynamic mutations that expand the CAG trinucleotide
repeat in the TBP gene have been identified to
cause spinocerebellar ataxia 17, a neurodegenerative
disorder [3]. However, there is no definite proof
to verify the correlation between the TBP gene and
hydrocephalus. Nonetheless, because a portion of the
cases of congenital hydrocephalus result from brain
deformity, we hypothesize that haploinsufficiency of
TBP, which might cause cortical dysplasia, could be
responsible for congenital hydrocephalus.
The PSMB1 gene is a multicatalytic protease
complex with a highly ordered ring-shaped 20S core
structure that is situated next to the TBP gene both in
humans and mice. The PSMB1 gene is tightly associated
with TBP as a functional unit in both species. On
this basis, PSMB1 and TBP appear to have similar genetic,
functional and pathological features [20]. Thus,
we suggest that PSMB1 and TBP may be additional
candidate genes for the congenital hydrocephalus
phenotype associated with the terminal 6q deletion.
Recently, the Quaking (QKI) gene that maps to
6q26 has been proposed to be associated with the
clinical phenotype of the 6q terminal deletion [3,21].
In humans, Aberg et al. [22] demonstrated that downregulation
of the QKI gene might cause a decline in
the mRNA levels of the myelin-related genes (PLP1,
MAG, and TF) that are involved in oligodendrocyte
differentiation and maturation in 55 schizophrenic
patients when compared with the controls, thus
indicating that QKI may play a role in myelin and
oligodendrocyte dysfunction in schizophrenia. In addition,
Backx et al. [21] reported the disruption of
the QKI gene in association with a de novo balanced
translocation resulting in a clinical phenotype similar
to the common subtelomeric 6q deletion syndrome,
though without seizures and brain anomalies. This
result suggests that haploinsufficiency of the QKI
gene underlies a substantial part of the 6q subtelomeric
deletion phenotype.
Deletion of QKI leads to dysmyelination defects,
and deletion of PARK2 co-regulated (Pacrg)contributes
to mild hydrocephalus [23]. Furthermore, the
communicating hydrocephalus phenotype can be rescued
by the transgenic expression of Pacrg in the qkv
mutant. Considering that the structure and function of
cilial systems is highly conserved between humans
and mice, we suggest that haploinsufficiency of the
human Pacrg gene located at 6q26 is responsible for
the congenital hydrocephalus phenotype.
A recent article reported that the smallest region
of overlap spans 1.7 Mb in 6q27 and contained DLL1,
THBS2, PHF10, and C6orf70 (ERMARD), which
are plausible candidates for the causation of structural
brain abnormalities [24]. DLL1 is expressed
in the paraxial mesoderm, which is correlated with
somito genesis in the nervous system [25]. PHF10
encoding a zing finger domain protein is essential for
self-renewal of the multipotent neural stem cells and
neuronal differentiation [24]. But the relationship between
these candidate genes and CNS abnormalities
is not sure, and the underlying pathogenicity is not
known. Maybe the molecular basis of these genes for
the disorder will be studied in the future. So here we
hypothesize the genes to be candidate genes.
A recent article reported seven patients and reviewed
14 patients in previous literature [24]. Here
we review 6q terminal deletion patients reported
with hydrocephalus and hemivertebrae present in
DECIPHER (Figure 5). From this figure, we can find
the patients who have the same phenotype as ours.
Moreover, their genotype in the 6q terminal deletion
is partially or totally similar to ours. So these can
nicely illustrate the deletion region that is responsible
for our patient’s phenotype.
In summary, we present a prenatal diagnosis
of a de novo partial monosomy 6q(6q25.3→qter)
by aCGH using uncultured amniocytes from a fetus
with congenital hydrocephalus and hemivertebrae.
To the best of our knowledge, this report describes
the largest detection of submicroscopic 6q terminal
deletions because of an atypical prenatal finding of
ventriculomegaly and hemivertebrae. We performed
a detailed investigation of the genotype-phenotype
correlations of the plausible candidate genes TBP,
PSMB1, QKI, Pacrg, and T with hydrocephalus and
hemivertebrae. Further investigation is required to
clarify the genetic mechanisms of the genes responsible
for the phe-notypic effects.
Declaration of Interest. This study was supported
by the grants from Guangdong Higher Education
Institutes of Science and the Technology Innovation
Project (2012 KJCX0087). The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of this article.
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