A large duplication involving the IHH locus mimics acrocallosal syndrome
- 11 January 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in European Journal of Human Genetics
- Vol. 20 (6), 639-644
- https://doi.org/10.1038/ejhg.2011.250
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.Keywords
This publication has 27 references indexed in Scilit:
- KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromesNature Genetics, 2011
- Copy-Number Variations Involving the IHH Locus Are Associated with Syndactyly and CraniosynostosisAmerican Journal of Human Genetics, 2011
- Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome-like phenotypeHuman Mutation, 2010
- Evolutionary toggling of the MAPT 17q21.31 inversion regionNature Genetics, 2008
- Polydactyly in the mouse mutant Doublefoot involves altered Gli3 processing and is caused by a large deletion in cis to Indian hedgehogMechanisms of Development, 2008
- Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactylyHuman Molecular Genetics, 2007
- IHH and FGF8 coregulate elongation of digit primordiaBiochemical and Biophysical Research Communications, 2007
- Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbsNature, 2002
- Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identityNature, 2002
- The Greig cephalopolysyndactyly syndrome: Report of a family and review of the literatureAmerican Journal of Medical Genetics, 1985