A new locus for split hand/foot malformation with long bone deficiency (SHFLD) at 2q14.2 identified from a chromosome translocation

Abstract

Split hand/foot malformation (SHFM) with long bone deWciency (SHFLD) is a distinct entity in the spectrum of ectrodactylous limb malformations characterised by associated tibial a/hypoplasia. Pedigrees with multiple individuals aVected by SHFLD often include nonpenetrant intermediate relatives, making genetic mapping diYcult. Here we report a sporadic patient with SHFLD who carries a de novo chromosomal translocation t(2;18)(q14.2;p11.2). Characterisation of the breakpoints revealed that neither disrupts any known gene; however, the chromosome 2 breakpoint lies between GLI2 and INHBB, two genes known to be involved in limb development. To investigate whether mutation of a gene in proximity to the chromosome 2 breakpoint underlies the SHFLD, we sought independent evidence of mutations in GLI2, INHBB and two other genes (RALB and FLJ14816) in 44 unrelated patients with SHFM, SHFLD or isolated long bone deWciency. No convincing pathogenic mutations were found, raising the possibility that a long-range cis acting regulatory element may be disrupted by this translocation. The previous description of a translocation with a 2q14.2 breakpoint associated with ectrodactyly, and the mapping of the ectrodactylous Dominant hemimelia mouse mutation to a region of homologous synteny, suggests that 2q14.2 represents a novel locus for SHFLD.

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

“…An apparently balanced de novo translocation with a breakpoint at 2q14.2 was identified in a patient with SHFM and holoprosencephaly (HPE) [Corona-Rivera et al, 2000]. A patient with SHFLD was later found to have a balanced translocation that also involved 2q14.2 [Babbs et al, 2007]. Although no genes were interrupted, the breakpoint was located within a region homologous to the Dominant hemimelia locus in mice.…”

“…Although no genes were interrupted, the breakpoint was located within a region homologous to the Dominant hemimelia locus in mice. Absence of mutations in several candidate genes in the region, including GLI2 and INHBB, in other patients with SHFM/SHFLD suggested that the translocation may have caused SHFLD through a position effect mechanism [Babbs et al, 2007]. A third balanced translocation involving 2q14.2 was identified in a fetus with isolated bilateral split-foot malformations [David et al, 2009].…”

Characterization of two ectrodactyly-associated translocation breakpoints separated by 2.5 Mb on chromosome 2q14.1–q14.2

“…The breakpoint associated with SFM was mapped to position 120 922 kb and colocalizes with a recently reported breakpoint associated with SHFLD. 11 The second breakpoint, associated with HHES, was mapped to position 118.4 Mb of chromosome 2, which is actually distal 2q41.1 and not 2q41.2. Several strong candidate genes were identified in these loci, including GLI2, INHBB, INSIG2 and EN1, which can all be easily correlated with Sonic Hedgehog (SHH) signalling and the observed phenotypes.…”

17p13.3 microduplications are associated with split-hand/foot malformation and long-bone deficiency (SHFLD)

“…Chromosome 2q14.2 has been implicated in a single individual with SHFLD arising from a de novo translocation without disrupting any known genes, but corresponding to the homologous region in mouse which gives rise to the 'dominant hemimelia' (Dh) limb malformation. 10 Both 1q42.2-q43 and 6q14.1, designated as loci SHFLD1 and SHFLD2, respectively, were shown to be linked to SHFLD in a large consanguineous Arab family. 11,12 SHFLD3 was mapped in a Brazilian family to an 861 kb interval at 17p13.1-17p13.3.…”