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Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired

Abstract

Holoprosencephaly (HPE) is the most common structural anomaly of the human brain and is one of the anomalies seen in patients with deletions and duplications of chromosome 13. On the basis of molecular analysis of a series of patients with hemizygous deletions of the long arm of chromosome 13, we have defined a discrete region in band 13q32 where deletion leads to major developmental anomalies (the 13q32 deletion syndrome). This approximately 1-Mb region1 lies between markers D13S136 and D13S147. Patients in which this region is deleted usually have major congenital malformations, including brain anomalies such as HPE or exencephaly, and digital anomalies such as absent thumbs2. We now report that human ZIC2 maps to this critical deletion region and that heterozygous mutations in ZIC2 are associated with HPE. Haploinsufficiency for ZIC2 is likely to cause the brain malformations seen in 13q deletion patients.

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Figure 1: Physical map of distal 13q32, showing YAC contig and ordered markers.
Figure 2: Genomic organization of ZIC2.
Figure 3: Predicted amino acid sequence and cross species comparison of ZIC2.
Figure 4: Tissue distribution of ZIC2 expression using multiple tissue northern blot analysis.
Figure 5: ZIC2 mutations in HPE patients.
Figure 6: HPE patient photographs.

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Acknowledgements

We thank the families who participated in this study. This work was supported in part by NIH grants HD32467 (S.B.), HD28732 and HD29862 (M.M.) and by the Divison of Intraamural Research, NHGRI, NIH (M.M.). We thank P. Jackey who provided valuable clinical material. In addition, we thank J. Chen, G. Asamani, J. Russo, P. Cserhalmi-Friedman and A. Christiano for their invaluable assistance with automated DNA sequencing.

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Correspondence to Stephen A. Brown.

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Brown, S., Warburton, D., Brown, L. et al. Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired . Nat Genet 20, 180–183 (1998). https://doi.org/10.1038/2484

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