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Keri Allen, Anne Michael Langguth, Kevin Linkroum, Maria Janessian, Danyi Wang, Elizabeth Delbono, Janey L Wiggs; CYP1B1 mutation carrier frequency in a normal population residing in the United States. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3806.
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CYP1B1 causes autosomal recessive congenital glaucoma world-wide. The incidence of congenital glaucoma varies among ethnic groups, with the highest incidence in Slovakian Gypsies (1/1,250) and the lowest in Western nations (1/10,000). Genetic testing can provide useful information for patients and families with congenital glaucoma; however, accurate risk assessment for recessive disorders requires information about the frequency of mutation carriers in the normal population. While CYP1B1 mutations are known to be responsible for 15-20% of congenital glaucoma cases in the United States (US), the CYP1B1 mutation carrier frequency in the normal US population has not been determined. The purpose of this study is to estimate the carrier frequency of CYP1B1 mutations in a population of clinically normal individuals residing in the US.
200 individuals (56% female, age 40-89, mean 65) without clinical evidence of glaucoma or a family history of glaucoma were enrolled. All subjects resided in the US. All CYP1B1 coding exons were sequenced (Sanger). DNA sequence variant pathogenicity was determined by Polyphen2 or a previous report of disease causality.
Based on the overall disease incidence (1/10,000) and prevalence of CYP1B1-related congenital glaucoma (15-20%) the incidence of CYP1B1-related congenital glaucoma in the US is approximately 1/50,000. Assuming Hardy-Weinberg distribution the expected CYP1B1 mutation carrier frequency would be 1/112 or 0.89%. Among the 200 normal individuals in this study, 11 (5.5%) are carriers of a single pathogenic mutation, representing a carrier frequency of 1/18 which is 6.4 times the expected frequency. A higher than expected carrier frequency (1/33,3.0%) was also observed in a population of 4300 Caucasian individuals sequenced as part of the NHLBI ESP project (evs.gs.washington.edu) where 127 pathogenic mutations were identified.
Our results suggest that the CYP1B1 mutation carrier frequency in the US population is between 1/18 and 1/33 which is 6.4 to 3.4 times the expected frequency. One explanation for this result is that CYP1B1 mutations can also cause glaucoma with later disease-onset not counted in the congenital glaucoma incidence estimations. Further study will be necessary to confirm this hypothesis; however, these results suggest that CYP1B1 genetic testing could be useful for other early-onset glaucomas as well as congenital glaucoma.
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