Exome-based mutation screening in South African children with primary congenital glaucoma
Nadia Carstens1, Saadiah Goolam2, Michaella Hulley1
1Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Insights
Whole exome sequencing identified pathogenic variants in CYP1B1 and TEK genes in South African children with primary congenital glaucoma (PCG). This genetic analysis offers insights into PCG etiology in this population.
Area of Science:
- Ophthalmology
- Genetics
- Genomics
Background:
- Primary congenital glaucoma (PCG) is a rare, severe form of glaucoma presenting at birth.
- Genetic factors play a crucial role in PCG pathogenesis, but causative mutations remain unidentified in many cases, particularly in diverse populations.
- Understanding the genetic basis of PCG is essential for diagnosis, genetic counseling, and potential therapeutic strategies.
Purpose of the Study:
- To identify pathogenic variants in South African children diagnosed with sporadic primary congenital glaucoma (PCG).
- To utilize whole exome sequencing (WES) for a comprehensive genetic analysis of PCG in this specific demographic.
- To investigate known and novel candidate genes associated with glaucoma and eye development.
Main Methods:
- Whole exome sequencing (WES) was performed on 23 black South African children with sporadic PCG.
- A prioritized variant analysis focused initially on known PCG genes (CYP1B1, LTBP2, TEK).
- Subsequent analysis involved identifying rare, potentially damaging variants in other eye-related genes using in silico predictions.
Main Results:
- Validated pathogenic variants were identified in the CYP1B1 gene (p.Arg390His) in one child and the TEK gene (p.Gly308Arg) in another child.
- No pathogenic variants in the LTBP2 gene were found in this cohort.
- Potentially damaging rare variants in other genes linked to eye development and glaucoma were detected in 12 additional children.
Conclusions:
- Whole exome sequencing is a valuable tool for diagnosing primary congenital glaucoma (PCG) in African children.
- This study reports the first disease-causing TEK variant in an African patient with PCG.
- Further investigation of candidate gene variants is warranted to fully elucidate the genetic landscape of PCG in this population.
Objectives:
To identify pathogenic variants in a cohort of 23 black South African children with sporadic primary congenital glaucoma (PCG) using an exome-based approach.
Methods:
Children with PCG were recruited from two Paediatric Ophthalmology Clinics in Johannesburg, South Africa. Whole exome sequencing was performed on genomic DNA. Of the 23 children, 19 were male and 19 had bilateral PCG. A variant prioritization strategy was employed whereby variants in known PCG genes (CYP1B1, LTBP2 and TEK) were evaluated first, followed by the identification of putative disease-causing variants in other genes related to eye diseases and phenotypes.
Results:
Validated pathogenic variants in the CYP1B1 gene (c.1169 G>A; p.Arg390His) and TEK gene (c.922 G>A; p.Gly308Arg) were identified in one child each. No LTBP2 mutations were identified in this cohort. In silico predictions identified potentially damaging rare variants in genes previously associated with eye development phenotypes or glaucoma in a further 12 children.
Conclusions:
This study demonstrates the value of whole exome sequencing in identifying disease-causing variants in African children with PCG. It is the first report of a TEK disease-causing variant in an African PCG patient. Potential causative variants detected in PCG candidate genes warrant further investigation.
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