Genomic organisation of the human chordin gene and mutation screening of candidate Cornelia de Lange syndrome genes.

We have determined the genomic organisation of the human chordin gene, CHRD, and have shown that it maps within a gene cluster at 3q27 containing THPO (thrombopoietin), CLCN2 (a voltage-gated chloride-channel gene) and EIF4G1 (a eukaryotic translation-initiation-factor-gamma gene). The CHRD and THPO genes are very close neighbours and are transcribed from opposing DNA strands from promoters that are spaced less than 2 kb apart. We considered that the CHRD gene and the chordin-regulating GSC (goosecoid) gene could be candidate genes for Cornelia de Lange syndrome (CDLS), a developmental malformation syndrome which is primarily characterised by mental handicap, growth retardation, distinctive facial features and limb-reduction defects. CDLS patients typically occur as sporadic cases, but several reports have suggested dominant inheritance. The candidacy of the CHRD and GSC genes was supported by several lines of evidence: prior evidence for a CDLS gene at 3q26.3-q27; a report suggesting a significant association between CDLS and thrombocytopenia; suspected genetic heterogeneity in CDLS; location of the GSC gene in close proximity to a 14q32 breakpoint detected in a CDLS patient with a balanced de novo translocation; known regulation of chordin expression by goosecoid; and the pattern of embryonic expression of the mouse GSC gene. Another candidate gene at 3q27, SOX2, was also considered because of its suspected role as a transcription factor in early development and because of known examples of SOX genes that are loci for dominantly inherited developmental disorders. However, mutation screening failed to identify CDLS patient-specific mutations in CHRD, GSC or SOX2.