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T. L. Yanovitch, S. F. Freedman, T. White, K.-N. Tran-Viet, R. Metlapally, W. Call, E. Burner, T. L. Young; CYP1B1, MYOC, and LTBP-2 Sequence Variations in a Cohort of Primary Congenital Glaucoma (PCG) Patients From the U.S.. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2179.
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Primary congenital glaucoma (PCG) is a rare and often devastating eye disease that can result in blindness. Inheritance is usually autosomal recessive in familial cases. Four genetic loci have been identified, and two main causative genes have been reported--the CYP1B1 gene (GLC3A locus) and the LTBP-2 gene (GLC3D locus). The MYOC gene has also been implicated in a few cases. The frequency of CYP1B, MYOC, and LTBP-2 mutations in a cohort of PCG subjects from the U.S. has not been reported. The purpose of this study was to screen patients from the U.S. with PCG for CYP1B1, MYOC, and LTPB-2 sequence variants.
PCG patients and family members were ascertained. PCG criteria were: (1) age of onset ≤ 3 years, (2) increased corneal diameter and/or corneal edema with Haab’s striae, (3) increased intraocular pressure > 21 mmHg, and/or (4) pathologic optic nerve cupping. Patients with other structural ocular abnormalities or systemic conditions were excluded. Genomic DNA was extracted from participant blood or saliva. Direct genomic sequencing of the CYP1B1, MYOC, and LTBP-2 genes was performed on proband DNA. Base pair comparisons were made with known reference sequences. Sequencing was also performed on DNA from 101 unaffected controls and family members of cases with identified sequence variants.
36 families were ascertained--50% (18/36) of cases were male, 52% (20/36) were Caucasian, 5% (2/36) were Hispanic, and 38% (14/36) were African American. Three of the cases had disease causing mutations in CYP1B1. One African American case was homozygous for a novel, coding non-synonymous (CNS) single nucleotide polymorphism (SNP) that resulted in a premature stop codon (R355X). Two Caucasian cases were compound heterozygotes with a 10 base pair insertion (rs72466463), and either a CNS SNP (rs55989760) or a novel CNS SNP. These SNPs caused missense mutations of E387K (lysine substituted for glutamic acid) and R390C (cysteine substituted for arginine), respectively. There were no disease-causing sequence variants found in MYOC or LTBP-2.
In our cohort, 3 cases (8%) had disease attributable to CYP1B1 mutations. There were no MYOC or LTBP-2 mutations associated with disease. The low percentage of sequence variant findings suggests that other genes are responsible for PCG in the U.S. population.
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