Abstract
BackgroundCongenital 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 presentationAnalysis 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.ConclusionsTo 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0316-0) contains supplementary material, which is available to authorized users.
Highlights
Congenital cataracts affect 3–6 per 10,000 live births and represent one of the leading causes of blindness in children
To the best of our knowledge, this is the first case reported in which disruption of the Glucosaminyl transferase 2 (GCNT2) gene does not involve the C isoform
Copy number variation analysis was completed by screening exome sequencing data using the Copy Number Inference From Exome Reads (CoNIFER) v0.2.2 software package as previously outlined [13]; regions of interest were further verified by independent quantitative PCR reactions using DNA samples from the proband and other available familial samples with SYBR Green PCR Master Mix (Applied Biosystems/Life Technologies, Carlsbad, CA, USA). qPCR reactions utilized three region-specific probes (Additional file 1: Table S1) and were performed as follows: primers located within regions of interest were designed using Primer3Plus software using qPCR settings
Summary
Congenital cataracts affect 3–6 per 10,000 live births and represent one of the leading causes of blindness in children. 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). Congenital cataracts are diagnosed within the first year of life These cataracts are one of the leading causes of blindness in children and are estimated to occur with a prevalence of 3–6 per 10,000 live births [1]. Recessive mutations in GCNT2 result in an adult i blood group phenotype, which is associated with congenital cataracts in some cases [7]. Seven missense mutations, one nonsense mutation, and two large deletions have been reported; mutations in exon 1C, affecting only the GCNT2C isoform, cause the adult i blood group without cataracts while mutations/deletions affecting exons 2 and 3, shared by all isoforms, result in the adult i blood group along with congenital cataract [7,8,9,10,11]
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