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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. BMC Med Genet 2016 Sep 08;17(1):64

Date

09/10/2016

Pubmed ID

27609212

Pubmed Central ID

PMC5016880

DOI

10.1186/s12881-016-0316-0

Scopus ID

2-s2.0-84986296839 (requires institutional sign-in at Scopus site)   6 Citations

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) of GCNT2 isoform A, the first exon (coding) of GCNT2 isoform B, and part of the intergenic region between GCNT2 and TFAP2A 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 in GCNT2 are known to cause an adult i blood group phenotype with congenital cataracts in some cases. The GCNT2 gene has three differentially expressed transcripts, with GCNT2B being the only isoform associated with lens function and GCNT2C 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 in TFAP2A 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 of TFAP2A cannot be ruled out.

CONCLUSIONS: To the best of our knowledge, this is the first case reported in which disruption of the GCNT2 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. The GCNT2-TFAP2A region may be prone to rearrangements through Alu-mediated non-homologous end-joining.

Author List

Happ H, Weh E, Costakos D, Reis LM, Semina EV

Authors

Deborah M. Costakos MD Chair, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cataract
Chromosome Breakpoints
Consanguinity
Exons
Female
Homozygote
Humans
Infant
Isoenzymes
Male
N-Acetylglucosaminyltransferases
N-Acetylhexosaminyltransferases
Pedigree
Sequence Deletion
Transcription Factor AP-2