American Journal of Medical Genetics Part C (Semin. Med. Genet.) 135C:69 – 76 (2005) A R T I C L E Non-multifactorial Neural Tube Defects SALLY ANN LYNCH* 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 INTRODUCTION 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: Sally.email@example.com 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. CHROMOSOME ANOMALIES Aneuploidies 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 70 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE TABLE I. Numerical Cytogenetic Abnormalities Associated With Isolated NTDs Aneuploidy SB 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 45,X Triploidy Tetraploidy þ Anencephaly Craniorachischisis Encephalocele Iniencephaly þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ References: Creasy and Alberman ; Byrne and Warbuton ; McFadden and Kalousek ; Rodriguez et al. ; Harmon et al. ; Lindor et al. ; Seller ; Hume et al. ; Coerdt et al. ; Hall and Solehdin ; Seller et al. 1998, 2004; Donaldson et al. . 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 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 Duplication SB 1q32-qter 2p23-2pter 3p21.3-p26a 3q21-qter 6q21-qter 7p 8q22-qter 8q24-qter 9q13-qter mosaic 11p 11qb 11q21-qter 13pter-q14 16p 20pter-p12 Tetrasomy 20p Xq26-27 þ þ þ þ Anencephaly Craniorachischisis Encephalocoele þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ References: Wright et al. ; Allderdice et al. ; Fear and Briggs ; Stamberg et al. ; Bader et al. ; Zumel et al. ; Schinzel ; Lurie et al. ; Winsor et al. ; Hol et al. ; Kennedy et al. ; Wellesley and Boyle ; Doray et al. ; Wu et al. . a Fetus had duplication of 3p21-p26 and a small deletion of 3p26 telomere. b Fetus partial trisomy 11q, partial monosomy 6p, phenotype result of either duplication or deletion. ARTICLE 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. AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) Duplications of 20pter-p12 have been described once in association with anencephaly [Zumel et al., 1989]. Helwig et al.  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, however. 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.  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.  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 71 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]. 72 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE TABLE III. Cytogenetic Deletions Associated With NTDs Deletions SB Anencephaly Craniorachischisis Encephalocoele þ 1q32q42 1q42-qter 2q24.3 2q35-36 3p26a 3q27-3qter 4pter-p16 5p15-pter 6pb 6q25.3 7q22.1-22.3 7q32-qter 7q36 þ þ þ þ þ þ þ þ þ þ þ Sacral agenesis & anterior meningocoele þ 13q33-34 18p 18qter 22q11 Xpter-p22.2 þ þ þ þ þ þ þ þ þ þ References: Mita et al. ; Telfer et al. ; Al-Awadi et al. ; Rudelli ; Jokiaho et al. ; Bogart et al. ; Melnyk and Muraskas ; Morichon-Delvallez et al. ; Plaja et al. ; Chen et al. ; Chinen et al. ; Nickel and Magenis ; Dowton et al. ; Nye et al. ; Kennedy et al. ; Luo et al. ; Lukusa et al. ; Rodriguez et al. . a Fetus had duplication of 3p21-p26 and a small deletion of 3p26 telomere. b 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 Ring SB Anencephaly 13 18 þ þ þ Craniorachischisis References: Jalal et al. ; Bird et al. ; Chen et al. . Encephalocoele þ þ with mental retardation and autism [Laumonnier et al., 2004]. SYNDROMES AND NTDs 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]. Anencephaly/Craniorachischisis 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 ARTICLE 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- AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ditions or those with unknown inheritance, and include Axelrod syndrome, Diprosopus, hemihypertrophyhemihypaesthesia-hemiareflexia-scoliosis, Medeira syndrome, meroanencephaly, schisis association, and XKaprosencephaly. Meningocele/Myelomeningocele 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 73 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. Encephaloceles 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, 74 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 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. SUMMARY Syndromic neural tube defects are a rare but important cause of NTD. 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