Mesomelic dysplasia Kantaputra type is associated with duplications of the HOXD locus on chromosome 2q

Abstract

Mesomelic dysplasia Kantaputra type (MDK) is characterized by marked mesomelic shortening of the upper and lower limbs originally described in a Thai family. To identify the cause of MDK, we performed array CGH and identified two microduplications on chromosome 2 (2q31.1-q31.2) encompassing B481 and 507 kb, separated by a segment of normal copy number. The more centromeric duplication encompasses the entire HOXD cluster, as well as the neighboring genes EVX2 and MTX2. The breakpoints of the duplication localize to the same region as the previously identified inversion of the mouse mutant ulnaless (Ul), which has a similar phenotype as MDK. We propose that MDK is caused by duplications that modify the topography of the locus and as such result in deregulation of HOXD gene expression. The ulnae are very short, and the radii are bowed. The distal humerus has a dumbbell shape, the hands are relatively normal but show progressive flexion contractures of the proximal interphalangeal joints. Carpal and tarsal synostoses are observed in some individuals. In the lower limbs, feet are fixed in plantar flexion with sole facing backward, causing 'ballerina-like standing' . The prominent distal fibula on the ventral aspect is a consistent feature and considered as the 'signature' finding of the syndrome. Calcaneus is small or missing. Small fibula and talus, and fibulo-calcaneal synostosis are characteristic features. Tibial bony knot articulates with the proximal end of the fibula. Since the original description, several other cases have been described that show similar changes. 3,4 In an Italian family with a mesomelic dysplasia, a balanced translocation t(2;8)(q31;p21) had previously been observed. 5,6 On the basis of the phenotypic similarities with MDK, chromosomes 2 and 8 were tested as candidate regions and a region on chromosome 2 (2q24-q32) spanning about 22.7 cM was identified to harbor the MDK gene. 7 Interestingly, this interval contains the HOXD cluster. However, sequencing of individual genes of the HOXD cluster revealed no mutation associated with MDK. We here describe genomic rearrangements including the entire HOXD cluster identified in the Thai family originally described by Kantaputra et al 1,2 as the likely cause for MDK.

Functional and topological characteristics of mammalian regulatory domains

“…lation in two important ways. It may help specify gene-enhancer interactions, and restrict ectopic ''enhancer adoption'' to accidental disruption of existing topologies, for example, through chromosomal rearrangements (Kokubu et al 2003;Spitz et al 2003;Niedermaier et al 2005;Gostissa et al 2009;Kantaputra et al 2010;Marini c et al 2013). Alternatively, it may help integrate the activity of multiple regulatory elements spread along large intervals (Carvajal et al 2001;Uchikawa et al 2003;Montavon et al 2011;Li et al 2012;Sanyal et al 2012;Shen et al 2012;Delpretti et al 2013;Marini c et al 2013;Visel et al 2013) into the coherent regulatory units that have been described as regulatory archipelagos, holo-enhancers or chromatin-hubs (Palstra et al 2003;Montavon et al 2011;Marini c et al 2013).…”

Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus

“…In addition to deletions, other rearrangements, such as inversions, translocations, or duplications involving sequences flanking the gene cluster, are observed in human patients, which are often linked to various limb anomalies (20)(21)(22)(23) (Fig. 1A).…”

Duplication at chromosome 2q31.1-q31.2 in a family presenting syndactyly and nystagmus

“…The 2q31.1 duplication in our cases was larger than that reported by the previous authors. 14, 11 We do not know whether our cases' phenotype is linked with increased gene expression or dysregulation at the HOXD locus. HOXD13 overexpression might explain the cutaneous syndac- Duplication at chromosome 2q31.1-q31.2 J Ghoumid et al tyly, although further expression studies in cells from the developing autopod, rather than in lymphoblasts, would be needed to ascertain this.…”

“…Recently, two reports on a dominant mesomelic dysplasia type Kantaputra have been described in association with a 2q31.1 duplication involving the HOXD locus and other genes (MTX2, EVX2, KIAA1715), out of which some are also known to have important roles during digit development. 14,11 The patients presented severe shortening of the middle segments of the arm, relative shortening of the tibia and fibula and no ophthalmologicalassociated anomaly. As our cases had a normal full skeletal survey, their phenotype is very different and is restricted to a bilateral cutaneous syndactyly between the third and fourth finger.…”

“…10 A disconnection of 5¢ Hoxd genes from the regulator could result in a downregulation of 5¢ Hoxd genes in the distal limb (autopod) and an upregulation in the proximal limb, and it has been suggested that the 2q duplication could have the same effect, therefore, explaining the mesomelic dysplasia recently reported. 11,4 Indeed, it has been recently reported that a 1 Mb microduplication of HOXD gene cluster at 2q31.1 is associated with a dominant mesomelic dysplasia, Kantaputra type. The condition is mainly affecting the upper limbs and is very variable among affected patients within the same family.…”