Case report of homozygous deletion involving the first coding exons of GCNT2 isoforms A and B and part of the upstream region of TFAP2A in congenital cataract. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Happ, Hannah; Weh, Eric; Costakos, Deborah; Reis, Linda; Semina, Elena
• Is Part Of: BMC medical genetics. Volume 17:Issue 1(2016)
• Page Start: 1
• Page End: 6
• Publication Date: 2016-12
• Subjects: GCNT2 deletion -- Congenital cataract -- Case report; Medical genetics -- Periodicals; 616.04205
• DOI: 10.1186/s12881-016-0316-0
• Languages: English
• ISSNs: 1471-2350

Abstract

Abstract Background Congenital cataracts affect 3–6 per 10, 000 live births and represent one of the leading causes of blindness in children. Congenital cataracts have a strong genetic component with high heterogeneity and variability. Case presentation Analysis of whole exome sequencing data in a patient affected with congenital cataracts identified a pathogenic deletion which was further defined by other techniques. A ~98-kb homozygous deletion of 6p24.3 involving the first three exons (two non-coding and one coding) ofGCNT2 isoform A, the first exon (coding) ofGCNT2 isoform B, and part of the intergenic region betweenGCNT2 andTFAP2A was identified in the patient and her brother while both parents were found to be heterozygous carriers of the deletion. The exact breakpoints were identified and revealed the presence of Alu elements at both sides of the deletion, thus indicating Alu-mediated non-homologous end-joining as the most plausible mechanism for this rearrangement. Recessive mutations inGCNT2 are known to cause an adult i blood group phenotype with congenital cataracts in some cases. TheGCNT2 gene has three differentially expressed transcripts, withGCNT2B being the only isoform associated with lens function andGCNT2C being the only isoform expressed in red blood cells based on earlier studies; previously reported mutations/deletions have either affected all three isoforms (causing blood group and cataract phenotype) or the C isoform only (causing blood group phenotype only). Dominant mutations inTFAP2A are associated with syndromic anophthalmia/microphthalmia and other ocular phenotypes as part of Branchio-Ocular-Facial-Syndrome (BOFS). While the patients do not fit a diagnosis of BOFS, one sibling demonstrates mild overlap with the phenotypic spectrum, and therefore an effect of this deletion on the function ofTFAP2A cannot be ruled out. Conclusions To the best of our knowledge, this is the first case reported in which disruption of theGCNT2 gene does not involve the C isoform. The congenital cataracts phenotype in the affected patients is consistent with the previously defined isoform-specific roles of this gene. TheGCNT2-TFAP2A region may be prone to rearrangements through Alu-mediated non-homologous end-joining.