Frequency of genomic rearrangements involving the SHFM3 locus at chromosome 10q24 in syndromic and non‐syndromic split‐hand/foot malformation

Abstract

Split-hand/foot malformation (SHFM), or ectrodactyly, is characterized by underdeveloped or absent central digital rays, clefts of the hands and feet, and variable syndactyly of the remaining digits. SHFM occurs as both an isolated finding and a component of many syndromes. SHFM is a heterogeneous condition caused by multiple loci, including SHFM1 (chromosome region 7q21-q22), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27), and SHFM5 (2q31). Mutations in TP63 at the SHFM4 locus are known to underlie both syndromic and non-syndromic forms SHFM, but the causes of most non-syndromic SHFM cases remain unknown. The recent identification of submicroscopic tandem chromosome duplications affecting the SHFM3 locus in seven families with non-syndromic SHFM has helped to further unravel the molecular basis of this malformation. In our ongoing studies of the SHFM3 locus in 44 additional cases of syndromic and non-syndromic SHFM, we have identified similar chromosome rearrangements in eight additional cases (18%), using pulsed-field gel electrophoresis (PFGE). We have also utilized real-time quantitative PCR (qPCR) to test for the duplications. Seven of the cases with rearrangements were non-syndromic. The current findings bring the total of SHFM3-associated cases with chromosome rearrangements to 15, which constitute 29% (15 of 51) of the cases screened to date. This includes 9 of 9 cases (100%) with known linkage to the SHFM3 locus, all of whom have non-syndromic SHFM, and 6 of 42 additional cases (14%), four of whom have non-syndromic SHFM. Thus, SHFM3 abnormalities underlie a substantial proportion of SHFM cases and appear to be a more frequent cause of non-syndromic SHFM than mutations in TP63.

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

“…The rearrangements were recurrent submicroscopic duplications ranging from 400-700 kb with similar, though not identical, breakpoints in and around FBXW4 and a region approximately 500 kb centromeric to FBXW4 [de Mollerat et al, 2003]. Subsequent studies of the SHFM3 locus have identified similar rearrangements in other familial and sporadic SHFM cases, most of which were nonsyndromal [Kano et al, 2005;Everman et al, 2006;Lyle et al, 2006]. Similar rearrangements were identified in patients with a syndromal form of SHFM variably associated with maxillary hypoplasia, micrognathia, renal hypoplasia, cleft palate, and hearing loss, previously described as the distal limb deficiencies-micrognathia syndrome (DLDMS; OMIM 246560) [Dimitrov et al, 2010].…”

Genetically regulated epigenetic transcriptional activation of retrotransposon insertion confers mouse dactylaplasia phenotype

“…Dactylaplasia is a mouse model of SHFM3 because the Dac locus is syntenic to the SHFM3 locus (10q24) (2, 6-9). Recently, 0.5-Mb tandem genomic duplications were identified at 10q24 in several SHFM3 families (10)(11)(12)(13). The smallest duplicated region contained a disrupted extra copy of the dactylin gene and the LBX1, BTRC, POLL, and DPCD genes in their entirety.…”

Identification of Critical Region Responsible for Split Hand/Foot Malformation Type 3 (SHFM3) Phenotype through Systematic Review of Literature and Mapping of Breakpoints Using Microarray Data

“…Abnormal bands were observed using pulsed-field gel electrophoresis in eight cases, all but one being non-syndromic reported by Everman et al in 2006 [4]. In all but one case, abnormal bands were observed with probes to the genes FBXW4 and BTRC and to the centromeric region approximately 400-kb upstream of FBXW4 .…”