Infant Glaucoma Phenotype Linked to Distinct Pathological Variant

April 6, 2010 Baby Blake Goldman’s eye is examined by Dr. Nasrin Tehrani at SickKids ophthalmology examination room. Premature infants face multiple complex challenges, including permanent blindness called Retinopathy of Prematurity (ROP), usually caused by the oxygen therapy they receive due to the immaturity of their lungs at delivery. Their retinas are at risk of detachment due to scarred tissue that develops from the oxygen therapy. SickKids has recently received new technology that lets doctors identify babies at risk of retinal damage and initiate surgical repair in a more timely fashion. Toronto Star/Andrew Wallace (Photo by Andrew Francis Wallace/Toronto Star via Getty Images)
In a study, 9 out of 13 newborns with glaucoma were homozygous for a distinct pathological variant.

Neonatal onset congenital ectropion uveae (NO-CEU), a distinct phenotype of newborn glaucoma, may represent a phenotypic marker for specific CYP1B1 genotypes, according to a study published in the American Journal of Ophthalmology.  

“Pathogenic variants in CYP1B1 may arrest the normal development of the trabecular meshwork (TM) and outflow systems, resulting in glaucoma,” according to the report.

Researchers sought to analyze the genetic variants of N0-CEU. The prospective cohort study included 13 infants with a diagnosis of NO-CEU who underwent clinical exome sequencing (CES). All children completed 1 year follow-up after glaucoma surgery. The mean and median age upon first surgery was 4.1+7.5 months and one month, respectively. The study defined the primary outcome as genetic variants found on CES, while considering the clinical indication of congenital glaucoma. 

The research team found that all 13 patients diagnosed with NO-CEU had developed glaucoma at birth and presented with severe bilateral disease. In total, 12 out of 13 (92.3%) patients carried CYP1B1 variants. Of these 12 patients, 9 (83.3%) were homozygous for the pathogenic variant [c.1169G>A(p.Arg390His)] in exon 3. These 9 patients experienced intractable glaucoma and subsequently needed multiple surgeries. The haplotype analysis of 6 patients with homozygous variants found 5 common homozygous single-nucleotide polymorphisms (SNPs) flanking c.1169G>A(p.Arg390His). 

A total of 6 patients experienced persistent corneal opacities, which required optical iridectomies. 

The team also found that 3 patients were compound heterozygous for CYP1B1 variants, exhibiting [c.1169G>A(p.Arg390His)], [c.1103G>A(p.Arg368His)], [c.1103G>A(p.Arg368His)], [c.1403_1429dup(p.Arg468_Ser476dup)], [(c.1063C>T(p.Arg355Ter)] and [c.1325del(p.Pro442GlnfsTer15)]. They noted that these specific patients had a more favorable visual prognosis. 

Study limitations include a relatively small sample size of patients, absence of a control group, and the testing may have missed other genes that harbor pathogenic variants.

“In the context of severe newborn glaucoma, where the corneal clouding may preclude accurate anterior segment assessment, candidate gene sequencing may prove to be helpful by detecting genetic variants, which would then point to the phenotype,” according to the investigators. “Both the phenotype and genotype could be beneficial to predictors of outcome and could help prognosticate this complex disease.” 


Kaushik S, Choudhary S, Kaur A, et al. Neonatal-onset congenital ectropion uveae may be caused by a distinct CYP1B1 pathological variant. Am J Ophthalmol. Published online January 23, 2022. doi:10.1016/j.ajo.2022.01.014