CYP1B1, MYOC, and LTBP2 Mutations in Primary Congenital Glaucoma Patients in the United States

Abstract

PURPOSE To screen primary congenital glaucoma patients in the United States for sequence variants within the CYP1B1, LTBP2, and MYOC genes using Sanger and whole exome sequencing. DESIGN Retrospective case-control study. METHODS Fifty-seven primary congenital glaucoma patients (47 families), 71 unaffected family members of the primary congenital glaucoma probands, and 101 healthy unrelated individuals were recruited from a single institution. Sanger sequencing of the primary congenital glaucoma gene, CYP1B1, was performed on 47 proband deoxyribonucleic acid samples. Simultaneously, whole exome sequencing was conducted on 3 families, each including more than 1 affected individual. Concurrently, 33 of 47 primary congenital glaucoma probands with extended family deoxyribonucleic acid samples were screened for LTBP2 and MYOC gene mutations. Exome-sequenced variations were validated by additional Sanger sequencing to confirm segregation of filtered disease-causing single nucleotide variations. RESULTS Seven primary congenital glaucoma families (14.9%) manifested disease phenotypes attributable to CYP1B1 mutations. One primary congenital glaucoma family possessed homozygous mutant alleles, whereas 6 families carried compound heterozygous mutations. Five novel combinations of compound heterozygous mutations were identified, of which 2 combinations were found with whole exome sequencing. No disease-causing mutations withinthe LTBP2and MYOCgenes were discovered. CONCLUSIONS This study analyzed CYP1B1, LTBP2, and MYOC mutations in a cohort of primary congenital glaucoma patients from the United States, applying whole exome sequencing as a complementary tool to Sanger sequencing. Whole exome sequencing, coupled with Sanger sequencing, may identify novel genes in primary congenital glaucoma patients who have no mutations in known primary congenital glaucoma genes.

Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

“…While PCG has clear genetic links, identification of causative alleles is complicated by variable disease penetrance and expressivity (5,9,12). Families identified in our patient cohort were no exception.…”

“…Indeed, PCG accounts for 18% of children enrolled in institutions for the blind worldwide (7). PCG occurs in all ethnic groups, but the disease incidence varies according to ethnic background, ranging from 1:1,250 in inbred populations to 1:30,000 in populations with heterogeneous ethnicity (6,(8)(9)(10)(11)(12). Families can exhibit autosomal recessive or dominant inheritance, although the majority of cases appear to be sporadic (5,6,(10)(11)(12)(13)(14).…”

Genetics of Primary Inherited Disorders of the Optic Nerve: Clinical Applications

“…In the United States, the incidence of congenital glaucoma is estimated to be approximately 1/10,000 (Fung et al 2013). CYP1B1 mutations are found in 20% of patients, whereas LTBP2 mutations are very rare (Lim et al 2013). Interestingly, in the United States the CYP1B1 mutation carrier frequency is three to five times higher than the incidence of congenital glaucoma would predict using Hardy-Weinberg distribution .…”

“…Approximately 20% of patients ascertained with earlyonset glaucoma through tertiary care facilities will have mutations in one of the genes known to cause early-onset glaucoma (Fig. 2) (Sena et al 2004;Lim et al 2013). Of these, mutations in FOXC1 are most common followed by MYOC, CYP1B1, PAX6, and PITX2.…”

Congenital glaucoma with anterior segment dysgenesis in individuals with biallelicCPAMD8variants

“…Depending upon the population, biallelic variants in CYP1B1 account for as few as 15% to as many as 100% of PCG cases 5,6 , with a prevalence of 22% among Australian cases 7 . LTBP2 variants are a rare cause of autosomal recessive congenital glaucoma and are often associated with megalocornea, spherophakia, and ectopia lentis 8 .…”