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K. F. Schilter, L. M. Reis, A. Schinzel, E. V. Semina; Deletion of Chromosome 18q23 and Its Link to Axenfeld-Rieger Syndrome. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1643.
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Axenfeld-Rieger syndrome is a complex disease featuring ocular malformations including anterior segment dysgenesis and glaucoma. The syndrome also often has extraocular features including abnormalities of the teeth and umbilical region. 18q deletion syndrome is a highly variable phenotype with a range of characteristics including mental retardation, short stature, hypotonia, hearing impairment, and foot deformities. We obtained a DNA sample from a patient with clinical features of congenital glaucoma, abnormal pupil and iris, deafness, abnormal teeth, and clubfeet. The patient was part of a pedigree with multiple features, which include congenital glaucoma.
The patient’s DNA was examined for mutations in several known ocular genes including CYP1B1 and PITX2 by direct DNA sequencing. Copy Number Variation (CNV) data was obtained by using the Affymetrix Genome-Wide Human SNP Array 6.0. The CNV results were confirmed by real-time PCR using the TaqMan Copy number assays by Applied Biosystems. Candidate genes within the deleted region are investigated for expression in zebrafish embryos by in situ hybridization.
Direct DNA sequencing of coding regions identified no mutations in CYP1B1 (congenital glaucoma) or PITX2 (Axenfeld-Rieger spectrum) genes in patient’s DNA. Whole genome screening of the sample for copy number alterations revealed a heterozygous 4.7-Mb deletion involving 18q23 region. The presence of the deletion was confirmed by TaqMan copy number assays. The deletion was not present in normal individuals based on analysis of 24 control samples and publicly available CNV data. Genes located in the deleted region were evaluated for their candidacy for the observed phenotype based on literature and database searches. Several genes such as SALL3, CTDP1, and ADNP2 were identified as candidates. Zebrafish orthologs of the candidate genes have been identified and are currently being analyzed for their role in embryonic development using expression and functional studies in zebrafish.
The 18q23 deletion was identified in a patient with a phenotypes showing significant overlap with the Axenfeld-Rieger spectrum. Consistent with the 18q deletion, the patient phenotype also includes hearing impairment and the foot deformities. Ocular anomalies however are not commonly seen in 18q deletion patients. The possibility of a second mutation in one of the genes within the deleted region that together with the deleted allele resulted in the recessive Axenfeld-Rieger phenotypes is being investigated.
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