Apresentação Científica do Centro de Genética Humana Instituto Nacional de Saúde Dr. Ricardo Jorge (INSA)
Split hand-split foot malformation (SHFM) or ectrodactyly, is a heterogeneous congenital defect of digit formation. The aim of this study is the mapping of the breakpoints and detailed molecular characterization of the candidate genes for an isolated form of bilateral split foot malformation (SFM) and for a syndromic form (holoprosencephaly, hypertelorism, and ectrodactyly syndrome (HHES)) both associated with de novo apparently balanced chromosome translocations involving the same chromosome 2q14.2 subband, [t(2;11)(q14.2;q14.2)] and [t(2;4)(q14.2;q35)], respectively.
Breakpoints were mapped by fluorescence in situ hybridisation (FISH) using BAC clones. Where possible, these breakpoints were further delimited using PCR fragments as FISH probes. The identified candidate genes were screened for pathogenic mutations by direct sequencing.
The SFM associated chromosome 2 breakpoint was localised at 120.9Mb, between the two main candidate genes, GLI-Kruppel family member GLI2 (GLI2) and inhibin beta B (INHBB). No clearly pathogenic mutation was identified in these. The second breakpoint associated with HHES was mapped 2.5Mb proximal at 118.4Mb and the candidate genes identified from this region were the insulin induced protein 2 (INSG2) and the homeobox protein engrailed-1 (EN1).
We have confirmed the presence of a new SHFM7 locus in the intergenic region between INHBB and GLI2. Furthermore, a locus for HHES is proposed 2.5Mb proximal to the previous one. The molecular mechanism proposed for these congenital anomalies is a sequence of alterations induced by the positional effects introduced by the translocations leading to dominant spatio-temporal misregulation of the candidate genes expression.
