Variable expressivity and high penetrance of CYP1B1 mutations associated with primary congenital glaucoma

To investigate penetrance and expressivity of CYP1B1 genotypes associated with primary congenital glaucoma (PCG).

Observational case series, systematic review, and comparative analysis of the literature.

Forty probands affected with PCG, 16 siblings affected with PCG, and 103 siblings and 75 parents of the probands reported not to be affected by history. The participants were members of 40 unrelated families.

Mutations were screened by restriction fragment length polymorphism, allele-specific polymerase chain reaction amplification, and direct sequencing. Ophthalmologic examination included slit-lamp biomicroscopy, intraocular pressure (IOP) measurement, gonioscopy, and high magnification stereoscopic fundus examination, followed by standard achromatic perimetry.

Identification of subjects carrying CYP1B1 mutations. Glaucoma diagnosis based on slit-lamp examination, IOP measurement, gonioscopic findings, optic nerve appearance, and perimetry.

Fifteen different homozygous or compound heterozygous mutant CYP1B1 genotypes were identified. Most probands and previously diagnosed subjects harbored G61E, R368H, R390H, and R469W mutations. Among the 178 apparently unaffected family members, 20 subjects from 12 families were observed to harbor 2 CYP1B1 mutations, suggesting an average penetrance of 73% for all the mutations. These 20 subjects ranged in age from 14 to 54 years. R390H appeared to have a notably high penetrance. Penetrance was 50% in the subset of families with incomplete penetrance. Ophthalmologic examination on 14 of the 20 apparently nonpenetrant individuals showed that 8 subjects were affected with juvenile open-angle glaucoma (JOAG) or primary open-angle glaucoma (POAG), and that 3 subjects were glaucoma suspect. One of the individuals with a JOAG diagnosis was the identical twin sibling of a proband affected with PCG.

At least 57% of the PCG nonpenetrant individuals examined clinically were affected with JOAG or POAG to varying degrees, and overall penetrance of "affected CYP1B1 genotypes" with respect to glaucoma may be more than 90%. These findings suggest that "affected CYP1B1 genotypes" exhibit variable expressivity rather than nonpenetrance. The clinical implication of this observation is that seemingly unaffected relatives of patients with PCG, particularly those known to harbor CYP1B1 mutations, should undergo regular ophthalmologic examination to allow early diagnosis.