Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1

Abstract

Background: Deletions that encompass 2q31.1 have been proposed as a microdeletion syndrome with common clinical features, including intellectual disability/developmental delay, microcephaly, cleft palate, growth delay, and hand/foot anomalies. In addition, several genes within this region have been proposed as candidates for split hand-foot malformation 5 (SHFM5). Methods: To delineate the genotype-phenotype correlation between deletions of this region, we identified 14 individuals with deletions at 2q31.1 detected by microarray analysis for physical and developmental disabilities. Results: All subjects for whom detailed clinical records were available had neurological deficits of varying degree. Seven subjects with deletions encompassing the HOXD cluster had hand/foot anomalies of varying severity, including syndactyly, brachydactyly, and ectrodactyly. Of 7 subjects with deletions proximal to the HOXD cluster, 5 of which encompassed DLX1/DLX2, none had clinically significant hand/foot anomalies. In contrast to previous reports, the individuals in our study did not display a characteristic gestalt of dysmorphic facial features. Conclusion: The absence of hand/foot anomalies in any of the individuals with deletions of DLX1/DLX2 but not the HOXD cluster supports the hypothesis that haploinsufficiency of the HOXD cluster, rather than DLX1/DLX2, accounts for the skeletal abnormalities in subjects with 2q31.1 microdeletions.

ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

“…We further demonstrated the conservative function of ClC-7 in the regulation of tooth formation. dlx2b belongs to distal-less (Dlx) family and plays a role in the development of forebrain, craniofacial and tooth 64 as well as split-hand/foot formation 65. The reduced dlx2b mRNA level might explain tooth malformation and tooth agenesis in clcn7 morphants, as well as tooth problems of osteopetrosis with CLCN7 mutations.…”

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

“…This locus was identified from reports of cytogenetically visible deletions involving 2q31 in patients with syndromal SHFM. Variable limb anomalies, including SHFM, have been described in association with a number of other findings, such as growth delay, developmental disability, microcephaly, cleft palate, craniofacial dysmorphism, seizures, and anomalies of the brain, eyes, heart, and genitalia [Benson et al, 1986;Ramer et al, 1990;Boles et al, 1995;Nixon et al, 1997;Del Campo et al, 1999;Goodman et al, 2002;Pescucci et al, 2007;Svensson et al, 2007;Davidsson et al, 2008;Tsai et al, 2009;Mitter et al, 2010;Dimitrov et al, 2011;Theisen et al, 2011]. The deletions associated with SHFM have varied in size, and most have been sporadic, but some familial cases have been described [Ramer et al, 1990;Del Campo et al, 1999].…”

“…With the advent of array CGH, a number of additional deletions involving 2q31.1 have been identified and characterized, and attempts have been made to localize the regions responsible for different phenotypic features, including limb anomalies [Pescucci et al, 2007;Svensson et al, 2007;Davidsson et al, 2008;Tsai et al, 2009;Mitter et al, 2010;Dmitrov et al, 2011;Theisen et al, 2011]. Although it has also been hypothesized that deletion of the DLX1 and DLX2 genes, which reside centromeric to EVX2 and the HOXD cluster, may cause SHFM and other limb anomalies, this was not supported in two recent reports, and it appears that deletions excluding the HOXD cluster and its regulatory regions are not sufficient to cause limb anomalies [Dimitrov et al, 2011;Theisen et al, 2011].…”

Chromosomal Imbalances in Patients with Congenital Cardiac Defects: A Meta-analysis Reveals Novel Potential Critical Regions Involved in Heart Development

“…39 Locus at 2q31.1 Duplication of chromosome 2q31.1 has been noted in a 3 generation family with mesomelic dysplasia, 40 but deletions involving 2q31.1 are relatively uncommon. 41 The predominant cardiac lesions in patients with 2q31.1 deletions that have been recorded in the databases are defects in cardiac septation resulting in ASDs and VSDs. Within the primary CR on chromosome 2q31 is CBF1interacting co-repressor (CIR1) ( Table 4B).…”