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

Abstract

HOXD genes encode transcription factors involved in the antero-posterior patterning of the limb bud and in the specification of fingers. During the embryo development, HOXD genes are expressed, following a spatio-temporal colinearity that involves at least three regions, centrometric and telomeric to this cluster. Here, we describe a father and a daughter presenting a 3-4 hand bilateral syndactyly associated with a nystagmus. Array-comparative genomic hybridisation showed a 3.8 Mb duplication at 2q31.1-q31.2, comprising 27 genes including the entire HOXD cluster. We performed expression studies in lymphoblasts by reverse transcription-PCR and observed an HOXD13 and HOXD10 overexpression, whereas the HOXD12 expression was decreased. HOXD13 and HOXD10 overexpression, associated with a misregulation of at least HOXD12, may therefore induce the syndactyly. Deletions of the HOXD cluster and its regulatory sequences induce hand malformations and, particularly, finger anomalies. Recently, smaller duplications of the same region have been reported in association with a mesomelic dysplasia, type Kantaputra. We discuss the variable phenotypes associated with such 2q duplications. European Journal of Human Genetics (2011) 19, 1198-1201; doi:10.1038/ejhg.2011.95; published online 8 June 2011Keywords: syndactyly; HOXD cluster; 2q31.1q31.2 duplication INTRODUCTION HOXD genes encode a family of highly conserved transcription factors involved in the antero-posterior patterning of the limb bud and in the specification of fingers. 1,2 During embryo development, HOXD genes are expressed following a spatio-temporal colinearity involving at least three regulatory regions, centrometric (ELCR) and telomeric (POST and Global Central Region (GCR)-Prox) to the cluster. 3 Moreover, these genes are expressed through two waves 4 during the limb budding, and control the patterning of the stylopod and the zeugopod. 5 The width and the efficiency of the genes' expression depend on their rank in the cluster. Each gene presents a precise pattern of expression. HOXD13, the most 5¢ end located gene, is highly expressed throughout the presumptive digits, whereas HOXD10, HOXD11 and HOXD12 are restricted to presumptive digit 2-5 and are underexpressed. In man, deletions of this cluster induce hand malformations and particularly finger anomalies. 5 Deletions of the whole cluster can cause severe defects, whereas deletions removing only HOXD9-HOXD13 are responsible for a milder phenotype including fifth finger clinodactyly, variable cutaneous syndactyly of toes, hypoplastic middle phalanges of the feet and synpolydactyly. 5,6 Deletions removing GCR are deleterious too, but induce minor anomalies. 7-9 ELCR has not been localised so far. Its role is so critical that deletions would be lethal and thus there is no animal model.Animal models carrying internal duplications of part of the HOXD cluster and limb anomalies exist. 3,4 Indeed, mice with targeted disruptions of Hoxd11 and Hoxa11 genes showed marked zeugopod malformation. 10 A disconnection of 5¢ Ho...

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

“…Two such duplications are associated with mesomelic dysplasia (a shortening of the forearm and lower leg), whereas a third and larger duplication causes syndactyly (fused digits) (21)(22)(23). Such distinct clinical outcomes as well as the present report illustrate the difficulty in elucidating those molecular mechanisms underlying the pathological consequences of complex genetic conditions in humans in the absence of a proper and adapted animal model.…”

“…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).…”

The Epidemiology, Genetics and Future Management of Syndactyly

“…It has also been found that minimal duplication does not seem to cause the phenotypical deformity [ 72 ]. Since its finding, HOXD13 has been linked with multiple limb deformities including SD type V, brachydactyly and syndromic forms of syndactyly [ 73 , 74 ].…”

Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster

“…Duplications of the HOXD cluster have been identified in rare patients. A 3.8 Mb large duplication at 2q31.1q31.2 comprising 27 genes including the entire HOXD cluster has been identified in a father and his daughter presenting with bilateral hand syndactyly and nystagmus [32]. A second patient with a 2q24.3q32.1 duplication presented with early-infantile-onset epilepsy, hypoplastic left heart syndrome, and global developmental delay [33].…”