Analysis of the Cat Eye Syndrome Critical Region in Humans and the Region of Conserved Synteny in Mice: A Search for Candidate Genes at or near the Human Chromosome 22 Pericentromere

Cat eye syndrome (CES, Online Mendelian Inheritance in Man (OMIM) no. 115470) is a rare developmental disorder in humans associated with the presence of three or four copies of a segment of chromosome 22q11.2, usually in the form of a bisatellited, isodicentric supernumerary chromosome (Schinzel et al. 1981; McDermid et al. 1986). CES is characterized by a variety of congenital defects including ocular coloboma, anal atresia, preauricular tags/pits, heart and kidney defects, dysmorphic facial features, and mental retardation (Schinzel et al. 1981). The penetrance and severity of these phenotypic features are highly variable. The smallest region of duplication required to produce the CES phenotype is the first 2 Mb of 22q (from the centromere to marker D22S57), as determined by analysis of a patient (25105) with all major features of the syndrome and an unusually small supernumerary dicentric ring chromosome (Mears et al. 1995). The 2-Mb CES critical region (CESCR) can be subdivided into ∼1-Mb proximal and distal halves (between markers D22S795 and D22S543) based on the proximal breakpoint of an interstitial duplication in patient “SK” (H. McDermid et al., in prep.). The CES features present in this patient (facial features, ear pits/tags, heart and kidney malformations, and mental retardation) (Knoll et al. 1995) should, therefore, map to the distal half of the CESCR. Absence of coloboma and anal atresia in this patient may be due to the phenotypic variability of the syndrome. To identify candidate genes for CES, the distal half of the CESCR was cloned in a contiguous array of bacterial and P1-based artificial chromosomes (BACs/PACs) (Johnson et al. 1999). A minimal overlapping set of clones from the region now has been sequenced and partially annotated with various ESTs and the genes IL-17R, ATP6E, and BID (Dunham et al. 1999). Here, we report the analysis of 14 putative genes within and adjacent to the distal 1.1 Mb of the CESCR. In addition, the sequence of a contiguous array of orthologous mouse genomic BAC clones revealed that 10 of these genes are present as a single linkage group on mouse chromosome 6. Sequence analysis of the proximal 400 kb of the human CESCR region revealed a complex mosaic of duplicated segments originating from elsewhere in the genome, similar to the pericentromeric regions of human chromosomes 16 (Horvath et al. 2000) and 10 (Jackson et al. 1999). The discovery of a 22q pericentromeric region transcript (CECR7), in which individual exons appear to be derived via duplication of gene sequences from different chromosomes, indicates this region may be the birth site of novel genes produced by shuffling of existing sequences.