Possible association of NTDs with a polyhistidine tract polymorphism in the ZIC2 gene

Abstract

Neural tube defects (NTDs) and brain malformations represent a common finding in chromosome 13q deletion patients. Hemizygosity for ZIC2, which is located in the 13q32 critical deletion region, results in holoprosencephaly (HPE) in humans, and diminished expression of ZIC2 results in HPE as well as lumbosacral NTDs in mice. Taken together, these observations led us to hypothesize that ZIC2 mutations may be a cause of isolated NTD. To test this, we screened 192 NTD patients for mutations in ZIC2. While we did not find ZIC2 mutations in these patients, we did find some evidence of a possible association between a histidine tract polymorphism in ZIC2 and NTDs. Our sample was too small to reach definitive conclusions, but the evidence is sufficiently intriguing to encourage further research. If this association is confirmed, subtle alterations in ZIC2 activity may confer a risk of NTD.

No association of the polyhistidine tract polymorphism of the ZIC2 gene with neural tube defects in a South American (ECLAMC) population

“…As only 3 cases presented mixed Native and AfricanAmerican backgrounds, we can consider our sample to be similar to the ethnic background described as Hispanic in North American studies (9,12).…”

“…The minimal deletion critical region includes 13q32, which is where the ZIC2 gene is located (3). Reduced or absent expression of Zic2 in mice is associated with holoprosencephaly (HPE), spina bifida, exencephaly, anencephaly and skeletal abnormalities (4); in humans, mutations in ZIC2 lead to HPE (5,6) and NTDs can be present in the patient or in the family (7)(8)(9)(10)(11).…”

“…The silent polymorphism c.1059C>T (H353) was studied in child-parent triads, but a transmission disequilibrium test showed no significant association with NTDs (10). An insertion of 70 bp within the first intron of ZIC2 was found in one NTD patient in a series of 192 cases, but the same mutation was found in the unaffected mother and sister of the proband (9). As well, a deletion of an alanine codon (c.94-96delGCG) in a polyalanine (pA) stretch inside the first exon of the ZIC2 gene was described in one male spina bifida patient out of 117 NTD cases from The Netherlands (10).…”

“…The possible association of another variant, the CAC repeat within the first exon of ZIC2, and an increased risk of nonsyndromic NTDs was proposed for patients with Hispanic ethnicity (9). However, this association was not observed in another Hispanic population (12), and the variant was not found in a population of Caucasian NTD cases (10).…”

Use of 3D Multislide CT in the Study of a Fetus with Cyclopia

“…A number of genes have been associated with holoprosencephaly and cyclopia, including Sonic Hedgehog (SHH) (Belloni et al, 1996;Chiang et al, 1996) ZIC2 (Brown et al, 2002), SIX3 (Wallis & Muenke, 1999) TGIF (Gripp et al, 2000), and others (Dubourg et al, 2007). Among the chromosomal abnormalities associated with cyclopia, trisomy 13 is the most common (Pachajoa et al, 2008), which was discarded in our patient by conventional karyotype, other abnormalities associated with holoprosencephaly are trisomy 18, triploidy, 7q deletion, and 18p deletion (Thakur et al, 2004;Pachajoa et al, 2007).…”