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Non-multifactorial neural tube defects.

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American Journal of Medical Genetics Part C (Semin. Med. Genet.) 135C:69 – 76 (2005)
Non-multifactorial Neural Tube Defects
Although most neural tube defects (anencephaly, spina bifida) occur as isolated malformations, a substantial
proportion are attributable to chromosome anomalies, known teratogens, or component manifestations of
multiple anomaly syndromes. This review describes known chromosome alterations and the candidate genes
residing in the altered region, as well as syndromes associated with neural tube defects and causative genes, if
known. ß 2005 Wiley-Liss, Inc.
KEY WORDS: anencephaly; spina bifida; chromosome deletion; chromosome duplication; candidate genes
The majority of neural tube defects
(approximately 70%) occur in isolation
and are said to show multifactorial
inheritance [Hall and Solehdin, 1998;
Aguiar et al., 2003]. However, reports
have suggested that between 2%–16%
of isolated NTDs will have a cytogenetic abnormality [Harmon et al.,
1995; Hume et al., 1996; Coerdt et al.,
1997]. Not surprisingly, this figure increases (up to 24%) if the neural tube
defect occurs in association with other
congenital abnormalities [Hume et al.,
1996]. Up to 53% of spontaneous abortions with a neural tube defect will have
a karyotypic abnormality [Creasy and
Alberman, 1976].
In addition, neural tube defects can
occur in association with other congenital anomalies and show a normal
karyotype. These types of neural tube
defects are described as syndromic
NTDs. Many are due to single gene
mutations and are inherited in autosomal
recessive, autosomal dominant, or Xlinked recessive manners. Some are
sporadic and are thought to result from
Sally Ann Lynch is a consultant clinical
geneticist at the National Centre for Medical
Genetics, Our Lady’s Hospital for Sick Children, Dublin, Ireland. She trained and
worked as a consultant geneticist in Newcastle-upon-Tyne, United Kingdom.
*Correspondence to: Sally Ann Lynch,
National Centre for Medical Genetics, Our
Lady’s Hospital for Sick Children, Crumlin,
Dublin 12, Ireland. E-mail:
DOI 10.1002/ajmg.c.30055
ß 2005 Wiley-Liss, Inc.
a teratogenic insult, e.g., maternal diabetes, antiepileptic medication; whereas
others have an unknown cause. Karyotype analysis and a thorough clinical or
postmortem examination of the child or
fetus are an essential part of the diagnostic process. These investigations will
help determine the etiology of neural
tube defect, i.e., whether it is multifactorial, chromosomal, or syndromic.
Identification of a chromosome
anomaly or syndrome diagnosis in a
child with a neural tube defect can lead to
more accurate provision of genetic
counseling to family members.
Identification of a
chromosome anomaly or
syndrome diagnosis in a
child with a neural tube
defect can lead to more
accurate provision of genetic
counseling to family members.
However, the study of these conditions
can also lead to identification of candidate genes and to understanding of the
mechanisms involved in neural tube
closure. For example, the association of
a neural tube defect with a particular
chromosome anomaly can lead to the
identification of candidate genes that
map within the deleted or duplicated
region. The identification of syndromecausing genes can also shed light on pos-
sible mechanisms of neural tube closure,
particularly when the gene’s function is
known. Despite all the promise of these
avenues of research, however, progress
has been slow. There are several reasons
for this slow pace: many syndromes are
exceptionally rare, obtaining samples
from affected cases is problematic, and
in some cases, syndromes are heterogeneous (e.g., Meckel syndrome). This
review, therefore, aims to summarize the
cytogenetic loci associated with neural
tube defects as a reference for possible
disease gene mapping within these loci.
The syndromes associated with NTDs
are also listed with reference to any
known loci or disease genes, and gene
function, if known.
Certain chromosomal anomalies are
more frequently associated with NTDs
than others [Seller, 1995] (Table I).
Trisomy 18 is the commonest aneuploidy associated with an NTD [Seller,
1995; Donaldson et al., 1999]. Trisomy
13 has been associated with spina bifida
and iniencephaly although it more
frequently presents with holoprosencephaly which is a distinct malformation of
the forebrain and is not traditionally
classified as an NTD [Rodriguez et al.,
1990; Seller, 1995]. However, an association between anencephaly and holoprosencephaly, which occurs more often
than one would expect by chance, has
TABLE I. Numerical Cytogenetic Abnormalities Associated With Isolated NTDs
Trisomy 2
Trisomy 7
Trisomy 8 mosaicism
Trisomy 9
Trisomy 11 mosaicism
Trisomy 13
Trisomy 14
Trisomy 15
Trisomy 16
Trisomy 18
Trisomy 20 mosaicism
Trisomy 21
References: Creasy and Alberman [1976]; Byrne and Warbuton [1986]; McFadden and Kalousek [1989]; Rodriguez et al. [1990]; Harmon
et al. [1995]; Lindor et al. [1995]; Seller [1995]; Hume et al. [1996]; Coerdt et al. [1997]; Hall and Solehdin [1998]; Seller et al. 1998, 2004;
Donaldson et al. [1999].
been described and is considered by
some as a severe variant of holoprosencephaly [Moore et al., 1996; Bird et al.,
1997]. Trisomy 9 has been described in
fetal losses with spina bifida on several
occasions [Lindor et al., 1995; Seller
et al., 1998].
Duplications of 2p23-pter commonly
occur with all types of associated NTDs
[Schinzel, 1994; Lurie et al., 1995;
Winsor et al., 1997a,b; Wellesley and
Boyle, 2000; Doray et al., 2003]. In
particular, 2p24 is thought to be the
susceptibility locus. Twelve genes map
to this area including the growth/
differentiation factor 7 gene (GDF7),
which is involved in the development of
certain cell types in the spinal cord [Lee
et al., 1998]; and DDEF2 (development
and differentiation enhancing factor 2)
which is involved in cell communication and structure, among other things
[Ishikawa et al., 1997].
In contrast, although numerous
duplications have all been reported in
association with a specific neural tube
defect (Table II) [Wright et al., 1974;
Allderdice et al., 1975; Fear and Briggs,
1979; Stamberg et al., 1981; Bader et al.,
TABLE II. Cytogenetic Duplications Associated With NTDs
9q13-qter mosaic
Tetrasomy 20p
References: Wright et al. [1974]; Allderdice et al. [1975]; Fear and Briggs [1979];
Stamberg et al. [1981]; Bader et al. [1984]; Zumel et al. [1989]; Schinzel [1994]; Lurie
et al. [1995]; Winsor et al. [1997]; Hol et al. [2000]; Kennedy et al. [2000]; Wellesley and
Boyle [2000]; Doray et al. [2003]; Wu et al. [2003].
Fetus had duplication of 3p21-p26 and a small deletion of 3p26 telomere.
Fetus partial trisomy 11q, partial monosomy 6p, phenotype result of either duplication
or deletion.
1984; Zumel et al., 1989; Schinzel,
1994; Kennedy et al., 2000; Wu et al.,
2003], neural tube defects are relatively
infrequent component manifestations of
these duplications, so it is difficult to
speculate the importance of these loci.
Neural tube defects are
relatively infrequent
component manifestations
of these duplications, so it
is difficult to speculate the
importance of these loci.
In addition, good candidate genes that
map within some of these regions have
not been identified. However, possible
candidates in the 3p region include cell
adhesion molecules (CNTN) 4 and 6
[Lee et al., 2000; Zeng et al., 2002] and
CHL1, a member of the L1 family of cell
adhesion molecules [Wei et al., 1998].
3q21-qter contains the Zic1 gene, which
is expressed in dorsal neural tube [Arriga
et al., 1994]. There is a HoxA cluster on
7p as well as other candidates including
lunatic fringe signaling protein (LFNG)
important for determining cell boundaries during development [Johnston
et al., 1997] and ZNF12, a member of
the zinc finger family of genes [Seite
et al., 1991]. Genes of interest that map
to 11q include the folate receptor gene
cluster, that includes an adult gene
(FOLR1), fetal gene (FOLR2), and
one or more pseudogenes [Ragoussis
et al., 1992]. Alterations of the FOLR1
gene have been found in some individuals with neural tube defects [De
Marco et al., 2000], but it is unclear
how overexpression of any of these genes
could cause NTD. Other genes that
map to this region include MKS2
(Meckel syndrome 2) and BarX2, a
homeobox gene important for development, particularly of neural and craniofacial structures [Jones et al., 1997].
Caudal type homeobox transcription
factor 2 (CDX2), involved in axial
elongation during mouse development
[Chawengsaksophak et al., 2004], is a
good candidate gene mapping to 13q.
Duplications of 20pter-p12 have been
described once in association with anencephaly [Zumel et al., 1989]. Helwig
et al. [1995] described a mouse with
spina bifida that was a double heterozygote for mutations in PAX1 and
PGDFRA. They suggested that digenic
interaction could be an important cause
of some congenital anomalies. In cases
such as 20p duplication, the gene interaction would be postulated to involve
overexpression of one of the genes, with
mutation in another gene. This scenario
has not yet been described.
Duplications of Xq27 have also
been reported with spina bifida [Hol
et al., 2000]. This duplication has been
well characterized and the putative gene
is thought to lie between DXS114 and
DXS1200, an area comprising about
13 Mb of DNA. There are no good
candidates within this region to date,
Deletions and
Ring Chromosomes
Various deletions and ring chromosomes
(Tables III–IV) have also been described in association with differing NTDs
[Mita et al., 1980; Al-Awadi et al., 1986;
Jokiaho et al., 1989; Melnyk and
Muraskas, 1993; Schinzel, 1994; Chinen
et al., 1996; Dowton et al., 1997; Nye
et al., 1998; Lukusa et al., 2001].
Chromosome regions discussed in the
section on duplications will not be rediscussed here.
As in duplications, NTDs are generally not common manifestations of
most of these deletions, so again it
is not clear what the significance is,
although here again digenic interaction
may be important. For example, Nye
et al. [1998] described two infants
with NTD and Waardenburg syndrome
type 3, who both had deletions of 2q3536.2. However, since it appears that
most individuals with this deletion do
not have NTD, a digenic etiology was
postulated. More recently, Kruger et al.
[2002] demonstrated that mice with
both Cbx1 and Pax3 mutations had
completely open neural tubes. They
suggested that Cbx1 and PAX3 acted
synergistically to promote neural tube
closure. SLIT2 is an obvious candidate
mapping to 4p15.2. Slit genes play a
crucial role in Drosophila CNS midline
formation. Human SLIT2 is exclusively
expressed in spinal cord [Itoh et al.,
1998] although the effect of gene
mutation is unknown. The IRX1 gene
and cadherin 18 gene map to chromosome 5p and are interesting candidates.
IRX1 is a member of the Iroquois
homeobox family of genes, that have
been found to be important during
mouse embryonic development of various structures, including the central
nervous system [Bosse et al., 1997];
cadherins are a family of calcium dependent cell–cell adhesion molecules that
may be important in neural development [Shibata et al., 1997]. Deletions of
7q36 have been described in association
with sacral agenesis and anencephaly [Bogart et al., 1990; MorichonDelvallez et al., 1993; Rodriguez et al.,
2002]. The HLXB9 gene maps here
and this causes Currarino syndrome or
triad, an autosomal dominant condition
which can present with an anterior
meningocoele and partial sacral agenesis
[Lynch et al., 2000]. The triad refers to
the fact that affected individuals may
present with sacral agenesis, a presacral
mass (anterior meningocoele and/or
teratoma) and anorectal malformation.
Sonic hedgehog also maps to 7q36 and
is the gene responsible for autosomal
dominant holoprosencephaly [Roessler
et al., 1996]. There have been rare reports describing anencephaly with 7q36.
It is likely that these cases have features of
holoprosencephaly as well and that the
malformation is the result of deletion of
the sonic hedgehog gene (SHH).
Deletions of 13q have been associated with spina bifida, encephaloceles,
and anencephaly [Telfer et al., 1980;
Rudelli, 1987; Chen et al., 1996; Luo
et al., 2000]. Ring chromosome 13 has
also been frequently associated with
NTDs presumably because the ring involves a 13q deletion [Jalal et al., 1990;
Chen et al., 2001]. The critical region
is reported to be 13q33-34. A strong
candidate gene for neural tube defect in
this region is the Zic5 gene, in that mice
with disrupted Zic5 show incomplete
neural tube closure [Inouye et al., 2004].
TABLE III. Cytogenetic Deletions Associated With NTDs
Sacral agenesis & anterior
References: Mita et al. [1980]; Telfer et al. [1980]; Al-Awadi et al. [1986]; Rudelli [1987]; Jokiaho et al. [1989]; Bogart et al. [1990]; Melnyk
and Muraskas [1993]; Morichon-Delvallez et al. [1993]; Plaja et al. [1994]; Chen et al. [1996]; Chinen et al. [1996]; Nickel and Magenis
[1996]; Dowton et al. [1997]; Nye et al. [1998]; Kennedy et al. [2000]; Luo et al. [2000]; Lukusa et al. [2001]; Rodriguez et al. [2002].
Fetus had duplication of 3p21-p26 and a small deletion of 3p26 telomere.
Fetus partial trisomy 11q, partial monosomy 6p, phenotype result of either duplication or deletion.
Other possible candidates for neural
tube defect within this region are G30
and G72, genes thought to predispose
to schizophrenia [Chumakov et al.,
2002]. Ring chromosome 18 has been
described with anencephaly occurring
in association with holoprosencephaly
[Bird et al., 1997]. The Zinc finger
protein gene, ZFP161, which is a candidate for HPE4 (Holoprosencephaly 4),
maps to 18p [Sobek-Klocke et al., 1997].
Deletions of 22q11 have been described in association with a sacral spina
bifida and congenital heart defects. This
combination had previously been called
Kousseff syndrome, although 22q11
deletion has been found to be the cause
of Kousseff syndrome thus it is no longer
a distinct entity [Nickel and Magenis,
1996; Seller et al., 2002]. Since spina
bifida is a relatively rare occurrence in
22q deletion, it is likely digenic mechanisms are responsible here as well.
Two candidates within this region include NLVCF and the Disheveled
1-like1 gene (DVL1L1) [Perrimon and
Mahowald, 1987; Funke et al., 1998].
Anencephaly has been described
with a deletion of Xpter-p22.1 [Plaja
et al., 1994]. Neuroligin 4 (NLGN4)
maps to this region. Mutations in this
gene have been reported in association
TABLE IV. Ring Chromosomes
References: Jalal et al. [1990]; Bird et al. [1997]; Chen et al. [2001].
with mental retardation and autism
[Laumonnier et al., 2004].
The London Dysmorphology database lists 16 syndromes associated with
anencephaly/craniorachischisis, 52 with
meningocoele/myelomeningocele, 20
with anterior encephalocele, and 43
associated with posterior encephalocele
[LDDB, 2001].
Of the 16 syndromes associated with
anencephaly, 5 are due to environmental
causes including maternal diabetes,
hyperthermia, fetal influenza, fetal aminopterin, and sodium valproate. Sodium
valproate is more traditionally associated
with spina bifida and it is difficult to be
sure whether the occasional cases reported with anencephaly in association with
sodium valproate intake are coincidental
or causal. The autosomal dominant
conditions are disorganization-like syndrome and brachydactyly C. Disorganization-like syndrome is thought to be a
semidominant trait with reduced penetrance and highly variable expression
[Robin et al., 1997]. Brachydactyly C
is caused by mutations in CDMP1
[Polinkovsky et al., 1997]. The link with
anencephaly is tenuous being based on
one affected female having a child
with anencephaly and brachydactyly
(type unknown) [Stagiannis et al.,
1995]. However, ectopic expression of
CDMP1 in the notochord, leading to
failure of vertebral body formation, has
been described in the mouse model
suggesting that the link with anencephaly may be causal. Acrocallosal, GrollHirschowitz, short rib-polydactyly type
2, and Zimmer syndromes are inherited in an autosomal recessive manner.
There have been several reports of
children with suspected acrocallosal syndrome and anencephaly suggesting this
is a causal relationship [Lurie et al., 1994;
Kedar et al., 1996]. The acrocallosal
phenotype is etiologically heterogeneous in that one child with suspected
acrocallosal syndrome was reported with
a mutation in the GLI3 gene [Elson et al.,
2002]. However, in other families GLI3
mutation have been excluded [Brueton
et al., 1992], and tentative linkage to 12p
suggested [Pfeiffer et al., 1992]. However, this mutation has not been found in
other cases, and the condition, or at least
the phenotype, is thought to be heterogeneous with the majority of cases
having mutations in as yet unknown
gene(s). Manouvrier syndrome is
thought to be an X-linked dominant
condition, whereas X-linked neural
tube defects is an X-linked recessive
condition. There have been a number of
reports describing anencephaly in
families with an X-linked pattern of
inheritance [Baraitser and Burn, 1984;
Toriello, 1984; Jensson et al., 1988].
Some of the families studied did not
show linkage to 62 markers on the
X chromosome suggesting that the
susceptibility gene maps elsewhere on
one of the autosomes [Hol et al., 1994;
Newton et al., 1994]. The other syndromic causes are either sporadic con-
ditions or those with unknown
inheritance, and include Axelrod syndrome, Diprosopus, hemihypertrophyhemihypaesthesia-hemiareflexia-scoliosis, Medeira syndrome, meroanencephaly, schisis association, and XKaprosencephaly.
Of the 52 conditions listed with meningocele or myelomeningocele as a feature, 7 are due to environmental factors
(cocaine, maternal diabetes, hyperthermia, thalidomide, valproate, vitamin A,
warfarin). Fifteen autosomal dominantconditions are listed, and include
anterior sacral defects, familial caudal
malformation syndrome, cleft lip/
palate-filiform fusion of eyelids, cranium
bifidum with NTD, Currarino triad,
Czeizel syndrome, DiGeorge sequence,
disorganization-like syndrome, Gollop
syndrome, Lehman syndrome, neurofibromatosis I, sacral agenesis-spina
bifida, one form of spondylocostal dysostosis, velocardiofacial syndrome, and
Waardenburg syndrome. Thirteen conditions are stated to be inherited as
autosomal recessive traits, and include
anophthalmia-clefting-neural tube defects, Fullana syndrome, GillessenKaesbach syndrome, Gollop syndrome,
Jarcho-Levin syndrome, Kennerknecht syndrome, limb/pelvis hypoplasia, Oculo-encephalo-hepato-renal
syndrome, PHAVER syndrome, SiegelBartlet syndrome, situs ambiguous, a
form of spondylocostal dysostosis, and
thrombocytopenia-absent radius syndrome. Two are thought to be X-linked
(Mathias laterality sequence, X-linked
neural tube defects). The remaining
conditions are either sporadic or of
unknown inheritance. However, many
of these syndromes are the result of a
small number of case reports and assigning an inheritance pattern is difficult.
Some of the listed single gene disorders
have, therefore, been assigned a tenuous
inheritance pattern. Where a syndrome
has been listed following one case report,
it is not clear if this condition is simply a
variant of a syndrome that has already
been described under a different name.
Such has been true for DiGeorge
syndrome and velocardiofacial syndrome, both the result of an identical
22q11 deletion, which are listed as two
separate entities despite being the same
condition. Currarino syndrome and
anterior sacral defects are also listed as
separate entities but are most likely the
same condition. The meningocele in
these two conditions is an anterior
meningocele and is quite distinct from
the more common posterior meningocele. HLXB9 (causing Currarino triad
and probably anterior sacral defects)
and ZIC3 (causing X-linked laterality and occasional sacral spina bifida)
are the only genes identified to date
resulting in a meningocele as part of a
syndromic phenotype.
Of the 20 entries with anterior encephalocele, 1 is thought to be due to
environmental factors (rubella), 2 are
inherited in an autosomal dominant
fashion (Apert syndrome, cranium bifidum with NTD), 4 are thought to be
autosomal recessive (craniotelencephalic
dysplasia, Kennerknecht syndrome,
homozygous acute intermittent porphyria, and Roberts syndrome), and 1 is
possibly inherited as an X-linked recessive entity (Boomerang dysplasia). The
remaining conditions are listed as sporadic or of uncertain inheritance. No
genes causing anterior encephalocele in
humans have been identified to date.
Of the 43 entries with posterior encephalocele as a feature, 3 are
due to environmental causes (cocaine,
hyperthermia, warfarin). Three conditions are inherited in an autosomal
dominant fashion (Goldenhar, PallisterHall, and Weissenbacher-Zweymuller
syndromes) and 19 are likely the
result of autosomal recessive inheritance (achondrogenesis 1, anophthalmiaclefting-neural tube defects, Arima
syndrome, craniomicromelic syndrome,
encephalocele-radial, cardiac, gastrointestinal, anal, and renal anomalies,
fronto-facio-nasal dysplasia, Fukuyama
congenital muscular dystrophy, Gershoni-Baruch syndrome, hydrolethalus
syndrome, Joubert syndrome, Kennerknecht syndrome, Keutel syndrome,
Knobloch-Layer syndrome, limb/pelvis
hypoplasia, Meckel-Gruber syndrome, oculo-encephalo-hepato-renal
syndrome, oral-facial-digital syndrome
type II, renal-hepatic-pancreatic dysplasia, Rolland-Desbuquois syndrome,
Silverman dwarfism, and Warburg syndrome). The inheritance pattern of the
remaining syndromes is uncertain.
Several genes for syndromes that
include posterior encephalocele as an
occasional finding have been identified to date. These include the DTDST
gene causing achondrogenesis type 1,
COL18AI causing Knobloch syndrome,
GLI3 causing Pallister-Hall, HSPG2
gene causing Silverman syndrome, and
POMT1 causing some cases of WalkerWarburg syndrome. Meckel-Gruber is
probably the most common syndromic
cause of a neural tube defect. Postaxial
polydactyly and cystic renal disease are
also commonly seen in Meckel-Gruber
patients. There are three different loci to
date, MKS1, MKS2, and MKS3 [Paavola
et al., 1995; Hentges et al., 2004].
PHOX2A maps to the MKS2 locus
on 11q and causes autosomal recessive
congenital fibrosis of the extra-ocular
muscles, but is also known to be expressed in the hindbrain in mice [Pattyn et al.,
1997], and therefore, may be a candidate
for MKS2.
Syndromic neural tube defects are a
rare but important cause of NTD. The
recurrence risk may be higher than that
for non-syndromic multifactorial NTD.
Syndromic neural tube defects
are a rare but important cause
of NTD. The recurrence risk
may be higher than that
for non-syndromic
multifactorial NTD.
A thorough clinical examination and
cytogenetic analysis is required on all
cases before determining recurrence
risks. Some of the causative genes
involved in syndromic NTD have been
identified allowing for a better understanding of the pathogenesis involved.
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