American Journal of Medical Genetics 124A:280–287 (2004) FOXC1 Gene Deletion Is Associated With Eye Anomalies in Ring Chromosome 6 Hui Z. Zhang, Peining Li, Dongmei Wang, Shannon Huff, Manjunath Nimmakayalu, Mazin Qumsiyeh, and Barbara R. Pober* Department of Genetics, Yale University School of Medicine, New Haven, Connecticut We report a case of ring chromosome 6 presenting with growth and mental retar- dation, cerebral dysgenesis, eye malforma- tions, mixed hearing loss, and abnormal physical features. Fluorescent in situ hybri- dization (FISH) and microsatellite geno- typing demonstrated segmental deletions of less than 6 Mb on 6p and 1–2 Mb on 6q. The primary karyotype is designated as 46,XY,r(6)(p25q27).ish r(6)(p25.1q27)(D6S344, FOXC1, D6S1574þ, D6S281, D6S297þ). Secondary structural and numerical vari- ants of the ring 6 were observed in 16% of the cells analyzed. Intragenic genotyping revealed deletion of the paternal FOXC1 gene, haploinsufficiency of which has been reported to cause eye anterior chamber developmental defects. Accordingly, we pro- pose that our patient’s ophthalmologic ab- normalities result from haploinsufficiency of the transcription factor FOXC1. We present clinical and cytogenetic summaries on 23 reported cases of ring 6 and categorize them into mild, moderate, and severely affected groups. Further phenotype comparisons be- tween cases with ring 6 and cases with only 6p or 6q terminal deletions suggest that genes important for hearing, vision, and central nervous system development remain to be identified in chromosome 6 terminal regions. Molecular definition of the fusion points and tissue mosaicism studies are necessary to better understand the geno- type–phenotype correlation of ring 6. We recommend ophthalmology, audiology, car- diology, and central nervous system exam- inations be part of the routine evaluation for children with a ring chromosome 6. ß 2003 Wiley-Liss, Inc. KEY WORDS: ring chromosome 6; FOXC1 gene deletion; eye anterior chamber anomalies; hearing loss INTRODUCTION Large human ring chromosomes are rare genetic abnormalities resulting from breakage and subsequent fusion of both end segments of the chromosome. Twenty- three cases of ring chromosome 6 have been reported in the literature since the initial description by Moore et al. [1973]. Patients with ring 6 have a wide range of phenotypes from growth delay accompanied by minimal or no mental retardation and few physical abnormal- ities, to profound growth and psychomotor retardation with multiple major congenital malformations involv- ing the ocular, auditory, cardiac, and central nervous systems. It has been suggested that tissue mosaicism, ring instability, and deletion size differences at both ends of the chromosome contribute to this phenotype variability. However, lack of molecular analysis of the ring chromosome fusion points hinders the effort to associate variable terminal segmental deletions with the range of phenotypic presentations. We are the first to perform phenotype and genotype correlations in a patient with ring 6 chromosome by defining the break- points and detecting deletion of the FOXC1 gene. The FOXC1 gene (previously referred to as FKHL7 or FREAC3), mapped to 6p25, is important for eye anterior chamber development, and mutations in this gene result in anomalies of the anterior chamber and congenital glaucoma [Mears et al., 1998; Nishimura et al., 2001]. We present cytogenetic and clinical find- ings of the 23 previously reported ring 6 cases, and compare their phenotypes to cases with terminal 6p or 6q deletions. These results bring new insights into the phenotypic variability among cases with ring chromosome 6. Grant sponsor: NIH; Grant number: T32-GM-08753. *Correspondence to: Barbara R. Pober, Department of Genetics, Yale University School of Medicine, New Haven, CT 06520. E-mail: barbara.pober@yale.edu Received 18 October 2002; Accepted 30 May 2003 DOI 10.1002/ajmg.a.20413 ß 2003 Wiley-Liss, Inc.