A large duplication involving the IHH locus mimics acrocallosal syndrome

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 B600-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 B900-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.

Structural Genome Variations Related to Craniosynostosis

“…This study has been corroborated by the observation of a duplication at the IHH locus in a patient with acrocallosal syndrome [Bochukova et al, 2009]. Moreover, a 900-kb duplication involving the entire IHH locus was found to mimic acrocallosal syndrome [Yuksel-Apak et al, 2012]. In a cohort of 182 Spanish craniosynostosis patients, a duplication of the IHH regulatory region was discovered in a patient with craniosynostosis Philadelphia type, which underscores the importance of IHH disruptions for cranial and skeletal development [Paumard-Hernán-dez et al, 2015].…”

Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions

“…Third, we studied a family that carries a heterozygous ~900 kb duplication in chromosomal region 2q35 that results in severe polysyndactyly and craniofacial abnormalities (Figure 1D) (Yuksel-Apak et al, 2012). The phenotype is reminiscent of the doublefoot ( Dbf ) mouse mutant, which also features massive polysyndactyly and was shown to be caused by a ~600 kb deletion affecting the same region (Babbs et al, 2008).…”

“…Heterozygous as well as homozygous newborns generated via tetraploid aggregation died shortly after birth of unknown cause and did not show overt limb phenotypes or other morphological defects (data not shown). Finally, we re-examined the previously described doublefoot ( Dbf ) mutant mouse strain due to the parallels in phenotype and genomic rearrangement with the human polydactyly patients (Figure 3D) (Yuksel-Apak et al, 2012). Dbf/+ mice have 6–9 digits per limb in a mirror image position with loss of anterior-posterior differences and no thumb-equivalent biphalangeal digit I (Figure 3F).…”

“…We hypothesized that this conservation allows for the analysis of disrupted regulatory interactions that occur in vivo during early embryonic development, using patient samples collected long after limb morphogenesis has ended. To test this approach, we performed 4C-seq in human adult fibroblasts from patients with the brachydactyly-associated deletion, the F-syndrome-associated duplication and the polydactyly-associated duplication (Yuksel-Apak et al, 2012). Fibroblasts from healthy control individuals showed interaction domains highly similar to wild-type developmental mouse limb buds, whereas patient fibroblasts recapitulated the aberrant interactions observed in the respective mutant mouse strains.…”

The Right Gene, Expressed at the Wrong Time, or at the Wrong Place

“…In patients with acrocallosal syndrome or craniosynostosis of the Philadelphia type, duplications at the IHH locus were detected [Yuksel-Apak et al, 2012;PaumardHernández et al, 2015]. Since the patient with craniosynostosis with the duplication encompassing the IHH regulatory region, the IHH encoding gene was thought to be involved in cranial and skeletal development [PaumardHernández et al, 2015].…”