Intrachromosomal duplications of 22q11 are not a common cause of isolated coloboma and coloboma with other limited features of cat eye syndrome

Abstract

Cateye syndrome(CES) is adevelopmental disorder with a variable pattern of congenital anomalies (OMIM #115470). CES is clinically characterized by uveoretinal coloboma, preauricular pits or tags, anal anomalies, total anomalous pulmonary venous return (TAPRV), or other congenital heart defects, renal malformations, craniofacial malformations, skeletal anomalies, and mental retardation. The variability of clinical manifestations is large, ranging from marginally affected individuals, to those with the full pattern of malformations and a lethal outcome [Berends et al., 2001; Rosias et al., 2001]. The majority of patients with CES carry a supernumerary bisatellited dicentric chromosome derived from chromosome 22 and described as dic(22) (pter!q11.2::q11.2!pter). This supernumerary chromosome results in the presence of four copies (tetrasomy) of 22p and proximal 22q11 in affected individuals. CES can also be caused by an interstitial duplication within 22q11, which produces three copies of the cat eye syndrome critical region (CESCR). This form of duplication has been less frequently described, possibly because the interstitial duplication may not always be visible by conventional cytogenetic or FISH analysis. Additionally, patients with only one extra copy of the CESCR might showevenmoreof a variablephenotype. They are likely to be mildly affected or to have only isolated features of CES [Taylor et al., 1977; Reiss et al., 1985; Knoll et al., 1995; Lindsay et al., 1995; Fujimoto and Lin, 1996]. Six patients with features of CES and interstitial duplications have been reported to date [reviewed in Meins et al., 2003]. Only a patient described by Meins et al. [2003] showed all the major symptoms of CES including coloboma, preauricular anomalies, heart defect, kidney malformation, and anal atresia. Although tetrasomy and especially trisomy for the CESCR does not always present with the classic CES phenotype, patients with limited and isolated features of the syndrome are not routinely tested for abnormalities in the 22q11 region. We hypothesized that some of these patients could carry small intrachromosomal duplications of the CESCR that are missed using current clinical testing methodologies. To test this hypothesis, we examined individuals with coloboma with or without other limited clinical features of CES for duplications involving the 22q11 critical region, knowing that uveoretinal coloboma represents a common feature of CES. Coloboma is present in 60% of the patients with supernumerary dic(22) chromosome [Rosias et al., 2001] and was detected in two out of six reported cases with an interstitial duplication of the CESCR. This eye defect has also been described in a patient with mosaic trisomy22 [Thomas et al., 2004]. Therefore, increased dosage of genes on chromosome 22 can disturb eye development and result in coloboma. Patients with ocular coloboma were referred to our research study by geneticists, genetic counselors, and ophthalmologists. Peripheral blood samples