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Tammy L. Yanovitch, Sharon F. Freedman, Khanh-Nhat Tran-Viet, Ravikanth Metlapally, Erica Burner, Whitney Call, Caldwell Powell, Terri L. Young; Candidate Gene Screening in a Cohort of Patients with Primary Congenital Glaucoma from the United States. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2417.
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Primary congenital glaucoma (PCG) is a potentially blinding eye disease that affects newborn infants and young children under three years of age. The incidence of PCG is relatively low (1:18,500 live births) in the U.S. To date, four loci (GLC3A, GLC3B, GLC3C, and GLC3D) and three genes (cytochrome P450, subfamily 1, polypeptide 1 [CYP1B1], latent transforming growth factor-beta-binding protein 2 [LTBP2], and myocilin [MYOC]) have been associated with PCG. Other PCG candidate genes include procollagen-lysine, 2 oxoglutarate 5 dioxygenase (PLOD1)-which has been implicated in Ehler Danlos syndrome with glaucoma/myopia phenotypes, and collagen type IV alpha 1 (COL4A1)-which has been implicated in mouse anterior segment dysgenesis. The purpose of this study was to perform candidate gene screening for sequence variants of PLOD1 and COL4A1 in patients with PCG from the U.S.
Genomic DNA from PCG subjects with their relatives, and unrelated controls was extracted from blood or saliva samples. Primer pairs were designed and direct Sanger sequencing was performed for the above candidate genes. Base pair comparisons were made with known reference sequences to identify sequence variants. Familial segregation analysis and control comparisons were used to confirm disease-causing sequence variants.
Fifty-two patients with PCG were enrolled in the study. All samples had been previously screened for mutations in CYP1B1, LTBP-2, and MYOC. In the 47 remaining patients, twelve novel variants were detected in PLOD1. Two of these were coding non-synonymous changes-a six base pair insertion in exon 5 and a transition in exon 7. Both novel variants were not found in over 600 control subjects without PCG. However, further investigation revealed that they did not follow segregation analysis with extended family members. Twenty-two novel variants were detected in COL4A1. Two of these were coding non-synonymous changes-one transition and one transversion. Both occurred in exons 30-31. Like PLOD1, these variants also did not follow segregation analysis.
In a cohort of 52 PCG subjects from the U.S., candidate gene screening of PLOD1 and Col4A1 was negative. The absence of sequence variant findings suggests that other genes and/or factors are responsible for PCG in the U.S. population.
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