FOXC1 gene deletion is associated with eye anomalies in ring chromosome 6.

We report a case of ring chromosome 6 presenting with growth and mental retardation, cerebral dysgenesis, eye malformations, mixed hearing loss, and abnormal physical features. Fluorescent in situ hybridization (FISH) and microsatellite genotyping 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-, D6S1574+, D6S281-, D6S297+). Secondary structural and numerical variants 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 propose that our patient's ophthalmologic abnormalities 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 between 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 genotype-phenotype correlation of ring 6. We recommend ophthalmology, audiology, cardiology, and central nervous system examinations be part of the routine evaluation for children with a ring chromosome 6. Copyright 2003 Wiley-Liss, Inc.