Neural tube defects are the second most common type of birth defect after congenital heart defects. The 2 most common NTDs are open spina bifida, also known as spina bifida cystica (SBC) or myelomeningocele, and anencephaly (206500) (Detrait ... Neural tube defects are the second most common type of birth defect after congenital heart defects. The 2 most common NTDs are open spina bifida, also known as spina bifida cystica (SBC) or myelomeningocele, and anencephaly (206500) (Detrait et al., 2005). Spina bifida occulta (SBO) is a bony defect of the spine covered by normal skin. It is mild form of spina bifida and is often asymptomatic. The term 'spinal dysraphia' refers to both SBC and SBO (Botto et al., 1999; Fineman et al., 1982). The most severe neural tube defect, craniorachischisis (CRN), leaves the neural tube open from the midbrain or rostral hindbrain to the base of the spine (summary by Robinson et al., 2012). An X-linked form of spina bifida has been suggested; see 301410. See also folate-sensitive neural tube defects (601634).
Fineman et al. (1982) studied 4 families in which multiple members had spina bifida cystica and/or spina bifida occulta. Excluding the probands, the frequency of all types of spinal/vertebral defects in family members was found to be 30/58 ... Fineman et al. (1982) studied 4 families in which multiple members had spina bifida cystica and/or spina bifida occulta. Excluding the probands, the frequency of all types of spinal/vertebral defects in family members was found to be 30/58 (52%). Statistical analysis indicated autosomal dominant inheritance with a penetrance of 75%. The authors concluded that both forms of spina bifida are different expressions of the same dominant gene in these kindreds. Spina bifida occulta was present in 15% of 100 control individuals. Fellous et al. (1982) reported a 5-generation family with spina bifida associated with sacral agenesis (see 600145). Abnormalities ranged from complete absence of the sacrum, with or without spina bifida aperta, to spina bifida occulta. The condition appeared in a man with 4 children who were all affected, and thereafter, to varying degrees, in 17 of his 28 descendants. The authors suggested autosomal dominant inheritance. Linkage analysis suggested a locus on chromosome 6 loci near PGM3 (172100) (lod score = 1.85 at a recombination fraction of 0.087). Nickel et al. (1994) reported 3 unrelated patients with 22q11 deletion syndrome, 2 with VCFS (192430) and 1 with DiGeorge syndrome (188400), who also had neural tube defects. However, in a follow-up study of 295 patients with spina bifida, Nickel and Magenis (1996) concluded that 22q11 deletion is an infrequent cause of NTD. - Reviews Botto et al. (1999) and Detrait et al. (2005) provided reviews of neural tube defects. De Marco et al. (2006) provided a detailed review of neurulation and the possible etiologies of neural tube defects.
Morrison et al. (1996) reported that an allelic variant of the T locus, referred to as TIVS7-2 (601637.0001), showed a bias in transmission from heterozygous parents to offspring with neural tube defects in Dutch and U.K. families. Shields ... Morrison et al. (1996) reported that an allelic variant of the T locus, referred to as TIVS7-2 (601637.0001), showed a bias in transmission from heterozygous parents to offspring with neural tube defects in Dutch and U.K. families. Shields et al. (2000) also found an association between the TIVS7-2 allele and neural tube defects. However, Trembath et al. (1999) and Speer et al. (2002) found no association. Jensen et al. (2004) observed that individuals carrying 1 or more copies of the TIVS7-2 allele have a 1.6-fold increased risk of spina bifida compared with individuals with 0 copies. Volcik et al. (2002) used the transmission disequilibrium test (TDT) to determine if genes in the PAX family play a role in the formation of NTDs; they performed further analysis with SSCA and direct sequencing. Although multiple variations were detected in each of the PAX genes with significant TDT results, the authors concluded that it is unlikely that these variations contribute to susceptibility for spina bifida. By analysis of HOX genes in 459 spina bifida patients and their parents, as well as within gene regions of 8 mouse models that exhibit NTDs, Volcik et al. (2002) obtained no significant findings with the markers tested. In a study of 144 patients with neural tube defects, Kibar et al. (2007) found mutations in 3 patients, 2 with a familial and 1 with a sporadic form of the disorder. The mutations were not found among 106 ancestrally matched controls or 65 control samples obtained from CEPH (Centre d'Etude du Polymorphisme Humain). The findings implicated variation in VANGL1, a human homolog of a Drosophila gene involved in establishing planar cell polarity, as a risk factor in neural tube defects. Lei et al. (2010) identified 3 different heterozygous missense mutations in the VANGL2 gene (see, e.g., 600533.0001 and 600533.0002) in 3 of 163 unrelated Chinese Han stillborn or miscarried fetuses with neural tube defects, including anencephaly. The authors postulated that loss of function defects in this gene have a lethal effect during in utero development in humans, and noted that mouse studies have indicated the loss of Vangl2 results in defects in neural tube closure. Kibar et al. (2011) sequenced the VANGL2 gene in a population-based study of 673 patients with various forms of neural tube defects. Six potentially pathogenic heterozygous missense mutations were identified in 7 patients, including 3 at positions that were absolutely conserved through zebrafish and Drosophila (R135W, R177H, and R270H), and 3 at positions that were highly conserved (L242V, T247M, and R482H). Two patients had open NTDs with myelomeningocele and 5 had closed NTDs, which was a statistically significant difference (p = 0.027). However, 2 unaffected parents carried 2 of the mutations, and another mutation (R105C) was found in 1 of 287 controls. Functional studies of the mutations were not performed. Kibar et al. (2011) suggested that variation in the VANGL2 gene may predispose to neural tube defects, but noted that the findings needed to be confirmed. Seo et al. (2011) found 5 missense mutations in the FUZZY gene (610622) among 234 Italian patients with neural tube defects. These sequence variants were absent in 130 matching Italian controls and over 250 control subjects sequenced as a part of the 1000 Genomes project. One mutation was found to interfere with ciliogenesis in 2 independent assays but did not affect cell directional movement. Another was found to have a striking effect on directional cell movement without affecting ciliogenesis, and a third mutation was found to affect both functions. For discussion of a possible role of variation in the PRICKLE1 gene in neural tube defects, see 608500.
Spina bifida and anencephaly are common birth defects, affecting 0.5 to 2 per 1,000 pregnancies worldwide. Craniorachischisis, the most severe neural tube defect, is considered rare, although estimates of prevalence range from 1 in 100,000 in the United ... Spina bifida and anencephaly are common birth defects, affecting 0.5 to 2 per 1,000 pregnancies worldwide. Craniorachischisis, the most severe neural tube defect, is considered rare, although estimates of prevalence range from 1 in 100,000 in the United States to 1 in 1,000 in northern China (summary by Robinson et al., 2012).