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Split hand/foot malformation (SHFM) with long bone deficiency (SHFLD) is a distinct entity in the spectrum of ectrodactylous limb malformations characterised by associated tibial a/hypoplasia. Pedigrees with multiple individuals affected by SHFLD often include non-penetrant intermediate relatives, making genetic mapping difficult. 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 deficiency. 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.

Original publication

DOI

10.1007/s00439-007-0390-7

Type

Journal article

Journal

Hum Genet

Publication Date

09/2007

Volume

122

Pages

191 - 199

Keywords

Abnormalities, Multiple, Base Sequence, Blotting, Southern, Chromosome Mapping, Chromosomes, Artificial, Bacterial, Chromosomes, Human, Pair 2, Computational Biology, DNA Mutational Analysis, DNA Primers, Foot Deformities, Congenital, Hand Deformities, Congenital, Humans, In Situ Hybridization, Fluorescence, Molecular Sequence Data, Nucleic Acid Hybridization, Tibia, Translocation, Genetic