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Identification and Management of a Novel PRDM5 Gene Pathologic Variant in a Family With Brittle Cornea Syndrome
Bonnie A Sklar1, Phattrawan Pisuchpen2, Mor Bareket3
1Department of Ophthalmology, Wills Eye Hospital, Philadelphia PA.
Insights
A novel PRDM5 gene variant causes brittle cornea syndrome (BCS) in three siblings, leading to severe eye problems like corneal thinning and scarring. This discovery aids in understanding BCS and its challenging surgical management.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- Brittle cornea syndrome (BCS) is a rare genetic disorder affecting the cornea.
- Understanding the genetic basis of BCS is crucial for diagnosis and management.
Observation:
- A nonconsanguineous Laotian family with three siblings diagnosed with BCS was studied.
- Ophthalmic examinations revealed myopia, blue sclerae, thin corneas, and variable corneal scarring in all affected siblings.
Findings:
- A novel homozygous PRDM5 gene variant (c.1117_1123delinsTTTAATGCTTACAAATGTTTG p.Asp373Phefs*57) was identified as the cause of BCS in this family.
- Histopathology of a sibling who underwent corneal transplant showed severe corneal thinning, absence of Bowman layer, and Descemet membrane abnormalities.
- No other pathogenic variants in PRDM5 or ZNF469 were found in the affected individuals.
Implications:
- This novel PRDM5 variant is strongly associated with BCS, supporting its pathogenicity.
- The findings highlight the genetic heterogeneity of BCS and the importance of PRDM5.
- Surgical interventions for BCS are complex due to extreme tissue fragility.
Purpose:
The aim of this study was to report a novel PRDM5 pathologic variant and ophthalmic findings in a family with 3 children diagnosed with brittle cornea syndrome (BCS). Histopathologic findings and surgical outcome of a child with BCS who underwent full-thickness corneal transplant are described.
Methods:
This is an observational case report of a nonconsanguineous Laotian family with 3 siblings diagnosed with BCS. Data collected included visual acuity, cycloplegic refraction, slit-lamp biomicroscopy, dilated fundus examination, corneal pachymetry, corneal topography, and general medical findings. Targeted testing through PRDM5 gene sequencing with copy number variation detection was conducted.
Results:
The 3 siblings included a 12-year-old boy and 8- and 6-year-old sisters, all of whom presented with myopia, blue-tinted sclerae, thin corneas, and variable corneal scarring. All 3 affected children were found to be homozygous for the PRDM5 gene variant c.1117_1123delinsTTTAATGCTTACAAATGTTTG p.Asp373Phefs*57. Coding sequences of PRDM5 and ZNF469 genes were sequenced in their entirety, and this was the only pathologic variant present in this family. The youngest affected sister developed persistent hydrops with severely decreased vision and underwent penetrating keratoplasty. Histopathology revealed severe corneal thinning, diffuse absence of Bowman layer, and ruptured Descemet membrane scrolls.
Conclusions:
Three siblings with clinical signs of BCS, including corneal thinning, myopia, and blue sclerae, were found to have a novel PRDM5 gene pathologic variant. This pathologic variant has not been previously reported, although 1 downstream nonsense pathologic variant has been reported as pathogenic. The similar phenotypes in all affected patients support the pathogenicity of this variant. Surgical management of BCS presents unique challenges due to severe tissue fragility.
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