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 stra nds 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 can didate genes for Cornelia de Lange syndrome (CDLS), a developmental malform ation syndrome which is primarily characterised by mental handicap, growth retardation, distinctive facial features and limb-reduction defects. CDLS p atients typically occur as sporadic cases, but several reports have suggest ed dominant inheritance. The candidacy of the CHRD and GSC genes was suppor ted by several lines of evidence: prior evidence for a CDLS gene at 3q26.3- q27; a report suggesting a significant association between CDLS and thrombo cytopenia; suspected genetic heterogeneity in CDLS; location of the GSC gen e 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 su spected role as a transcription factor in early development and because of known examples of SOX genes that are loci for dominantly inherited developm ental disorders. However, mutation screening failed to identify CDLS patien t-specific mutations in CHRD, GSC or SOX2.