Abstract
Split hand-split foot malformation or ectrodactyly is a heterogeneous congenital defect of digit formation. The aim of this study is the mapping of the breakpoints and a detailed molecular characterization of the candidate genes for an isolated and syndromic form of ectrodactyly, both associated with de novo apparently balanced chromosome translocations involving the same chromosome 2 band, [t(2;11)(q14.2;q14.2)] and [t(2;4)(q14.1;q35)], respectively. Breakpoints were mapped by fluorescence in situ hybridization using bacterial artificial chromosome clones. Where possible, these breakpoints were further delimited. Candidate genes were screened for pathogenic mutations and the expression levels of two of them analysed. The isolated bilateral split foot malformation-associated chromosome 2 breakpoint was localized at 120.9 Mb, between the two main candidate genes, encoding GLI-Kruppel family member GLI2 and inhibin-βB. The second breakpoint associated with holoprosencephaly, hypertelorism and ectrodactyly syndrome was mapped 2.5 Mb proximal at 118.4 Mb and the candidate genes identified from this region were the insulin-induced protein 2 and the homeobox protein engrailed-1. No clear pathogenic mutations were identified in any of these genes. The breakpoint between INHBB and GLI2 coincides with a previously identified translocation breakpoint associated with ectrodactyly. We propose a mechanism by which translocations in the 2q14.1–q14.2 region disrupt the specific arrangement of long-range regulatory elements that control the tight quantitative spatiotemporal expression of one or more genes from the breakpoint region.
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Acknowledgements
We thank Purificação Tavares for pre-natal diagnosis of the translocation; Anabela L Dias for maintaining the LCL; Catarina Reis for contributing to the screening of the 5′UTR of INHBB; Sara Malveiro for contributing to fine mapping of the chromosome 2 breakpoint; Emine Bolat for quantitative RT-PCR analysis; Paula Borralho and Ricardo Laurini, for morphopathological evaluation of the abortus; and Raoul Hennekam for contributing patient material. This project was partially supported by Fundação para a Ciência e a Tecnologia research Grant POCTI/MGI/38649/2001, by Programa de Financiamento Plurianual do CIGMH and by Fundo Comunitário Europeu FEDER, and the European Union Sixth Framework program EpiStem project (LSHB-CT-2005-019067).
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David, D., Marques, B., Ferreira, C. et al. Characterization of two ectrodactyly-associated translocation breakpoints separated by 2.5 Mb on chromosome 2q14.1–q14.2. Eur J Hum Genet 17, 1024–1033 (2009). https://doi.org/10.1038/ejhg.2009.2
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DOI: https://doi.org/10.1038/ejhg.2009.2
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