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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

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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.

Electronic supplementary material: The online version of this article (doi:10.1186/s12881-016-0316-0) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus

Patient photographs and pedigree. a Photograph of Patient 1’s eyes at 2 months of age showing bilateral cataract. b Pedigree showing both affected siblings with a homozygous deletion of 6p24.3 while the unaffected parents are heterozygous carriers. WT: wild type; black arrow indicates proband
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Fig1: Patient photographs and pedigree. a Photograph of Patient 1’s eyes at 2 months of age showing bilateral cataract. b Pedigree showing both affected siblings with a homozygous deletion of 6p24.3 while the unaffected parents are heterozygous carriers. WT: wild type; black arrow indicates proband

Mentions: Patient 1(individual II:1) is an 18-month old Pakistani female affected with bilateral dense central congenital cataract (Fig. 1a, Table 1) which were visually significant and required extraction at 2 months of age, mild asymmetry of the palpebral fissures, and left nasolacrimal duct obstruction; her development is normal and growth parameters are generally normal with the exception of borderline microcephaly (length 83.8 cm, 75–90th centile; weight 10.2 kg, 25–50th centile; and head circumference 44 cm (3rd centile)). Physical exam at 4 months of age identified hypotelorism (familial) and mildly widely-spaced nipples. Her younger brother, age 6 months, was similarly affected with visually significant bilateral dense central congenital cataracts requiring extraction around 2 months of age; his length (67.5 cm, 25–50th centile), weight (6.8 cm, 5–10th centile), and head circumference (42.5 cm, 10–25th centile) are all within the normal range (Table 1). Family history shows unaffected second-cousin parents with additional endogamous mating within the family. A double second-cousin to the proband is affected with bilateral non-syndromic anophthalmia/ microphthalmia with no additional details available.Fig. 1


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
Patient photographs and pedigree. a Photograph of Patient 1’s eyes at 2 months of age showing bilateral cataract. b Pedigree showing both affected siblings with a homozygous deletion of 6p24.3 while the unaffected parents are heterozygous carriers. WT: wild type; black arrow indicates proband
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Related In: Results  -  Collection

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Fig1: Patient photographs and pedigree. a Photograph of Patient 1’s eyes at 2 months of age showing bilateral cataract. b Pedigree showing both affected siblings with a homozygous deletion of 6p24.3 while the unaffected parents are heterozygous carriers. WT: wild type; black arrow indicates proband
Mentions: Patient 1(individual II:1) is an 18-month old Pakistani female affected with bilateral dense central congenital cataract (Fig. 1a, Table 1) which were visually significant and required extraction at 2 months of age, mild asymmetry of the palpebral fissures, and left nasolacrimal duct obstruction; her development is normal and growth parameters are generally normal with the exception of borderline microcephaly (length 83.8 cm, 75–90th centile; weight 10.2 kg, 25–50th centile; and head circumference 44 cm (3rd centile)). Physical exam at 4 months of age identified hypotelorism (familial) and mildly widely-spaced nipples. Her younger brother, age 6 months, was similarly affected with visually significant bilateral dense central congenital cataracts requiring extraction around 2 months of age; his length (67.5 cm, 25–50th centile), weight (6.8 cm, 5–10th centile), and head circumference (42.5 cm, 10–25th centile) are all within the normal range (Table 1). Family history shows unaffected second-cousin parents with additional endogamous mating within the family. A double second-cousin to the proband is affected with bilateral non-syndromic anophthalmia/ microphthalmia with no additional details available.Fig. 1

View Article: PubMed Central - PubMed

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.

Electronic supplementary material: The online version of this article (doi:10.1186/s12881-016-0316-0) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus