Abstract
Indian hedgehog (Ihh) signaling is a major determinant of various processes during embryonic development and has a pivotal role in embryonic skeletal development. A specific spatial and temporal expression of Ihh within the developing limb buds is essential for accurate digit outgrowth and correct digit number. Although missense mutations in IHH cause brachydactyly type A1, small tandem duplications involving the IHH locus have recently been described in patients with mild syndactyly and craniosynostosis. In contrast, a ∼600-kb deletion 5′ of IHH in the doublefoot mouse mutant (Dbf) leads to severe polydactyly without craniosynostosis, but with craniofacial dysmorphism. We now present a patient resembling acrocallosal syndrome (ACS) with extensive polysyndactyly of the hands and feet, craniofacial abnormalities including macrocephaly, agenesis of the corpus callosum, dysplastic and low-set ears, severe hypertelorism and profound psychomotor delay. Single-nucleotide polymorphism (SNP) array copy number analysis identified a ∼900-kb duplication of the IHH locus, which was confirmed by an independent quantitative method. A fetus from a second pregnancy of the mother by a different spouse showed similar craniofacial and limb malformations and the same duplication of the IHH-locus. We defined the exact breakpoints and showed that the duplications are identical tandem duplications in both sibs. No copy number changes were observed in the healthy mother. To our knowledge, this is the first report of a human phenotype similar to the Dbf mutant and strikingly overlapping with ACS that is caused by a copy number variation involving the IHH locus on chromosome 2q35.
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Acknowledgements
We thank the family members for participating in this study, Dr M Kalff-Suske for molecular genetic testing of GLI3 in our patient and Karin Boss for critically reading the manuscript. This work was supported by the German Federal Ministry of Education and Research (BMBF) by grant number 01GM0880 (SKELNET) and 01GM0801 (E-RARE network CRANIRARE) to BW and the Turkish Council of Science (TUBİTAK) by grant number 108S418 (E-RARE network CRANIRARE partner 4) to HK and OU.
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Yuksel-Apak, M., Bögershausen, N., Pawlik, B. et al. A large duplication involving the IHH locus mimics acrocallosal syndrome. Eur J Hum Genet 20, 639–644 (2012). https://doi.org/10.1038/ejhg.2011.250
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DOI: https://doi.org/10.1038/ejhg.2011.250
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