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

• Published in: Human genetics Vol. 122; no. 2; pp. 191 - 199
• Main Authors: BABBS, Christian, HELLER, Raoul, EVERMAN, David B, CROCKER, Mark, TWIGG, Stephen R. F, SCHWARTZ, Charles E, GIELE, Henk, WILKIE, Andrew O. M
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01-09-2007; Berlin Springer Nature B.V; New York, NY
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Base Sequence; Biological and medical sciences; Blotting, Southern; Chromosome aberrations; Chromosome Mapping; Chromosomes, Artificial, Bacterial; Chromosomes, Human, Pair 2 - genetics; Classical genetics, quantitative genetics, hybrids; Computational Biology; Developmental biology; DNA Mutational Analysis; DNA Primers - genetics; Foot Deformities, Congenital - genetics; Foot Deformities, Congenital - pathology; Fundamental and applied biological sciences. Psychology; Genes; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Hand Deformities, Congenital - genetics; Hand Deformities, Congenital - pathology; Human; Humans; In Situ Hybridization, Fluorescence; Inhibin; Medical genetics; Medical sciences; Molecular Sequence Data; Nucleic Acid Hybridization; Tibia - abnormalities; Tibia - pathology; Translocation, Genetic - genetics; Chromosomal aberration; Deficiency; Diseases of the osteoarticular system; Split-hand split-foot syndrome; Genetic disease; Osteoarticular system; Disease of the hand; Malformation; Disease of the foot; Abnormal chromosome; Genetics; Bone; Locus; Chromosome translocation
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-007-0390-7

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.