Genotype/Phenotype Correlation in Primary Congenital Glaucoma Patients in the Lebanese Population: A Pilot Study

Background: The incidence of primary congenital glaucoma (PCG) varies among geographic regions and ethnic groups. The frequency of PCG in Lebanon and identification of disease-causing mutations have not been studied previously.

Purpose: To investigate the role of Cytochrome P1B1 (CYP1B1) gene and Myocillin (MYOC) gene mutations in PCG in the Lebanese population and study possible genotype/phenotype correlations.

Methods: Patients with unilateral or bilateral PCG diagnosed at the American University of Beirut Medical Center and their first-degree relatives (parents and siblings) were screened for CYP1B1 and MYOC mutations. Demographic and phenotypic characteristics were recorded. Phenotypic characteristics pertaining to disease severity and outcomes were compared.

Results: Eighteen Lebanese families (66 subjects) with at least one member affected with PCG were included in this study. Mutations in the CYP1B1 gene were detected in 6 families (33%). Five previously described mutations (p.R444Q; p.E229K; p.R469W; p.G61E; p.M1T) and one new single nucleotide deletion were identified (1793delC). Patients in whom CYP1B1 mutations were detected tended to have a more severe phenotype as evidenced by earlier age at diagnosis, higher rate of bilateral disease, and higher number of glaucoma surgeries than those in whom no CYP1B1 mutations were present. MYOC gene mutations were not detected in any patients.

Conclusion: The rate of CYP1B1 mutations in Lebanese patients with PCG is lower than that reported in other Arab and Middle Eastern populations and suggests other genes are responsible for PCG in the remainder.     

AIPL1突变患者先天性Leber黑蒙表现型

目的：叙述26例先证者中芳香族羟基碳氢化合物受体蛋白样1蛋白质（AIPL1）突变的先天性Leber黑蒙（LCA）的表现型，并比较其他LCA相关性基因的表现型。叙述杂合子携带者的视网膜电图（ERG）。     

Novel Homozygous CYP1B1 Deletion in Siblings with Primary Congenital Glaucoma

ABSTRACT

Purpose: To retrospectively analyze the potential sources of error for IOL power calculation in patients with X-linked related megalocornea (XLMC).

Methods: Case report and comparative analysis of refractive outcomes in previously reported phacoemulsification procedures in XLMC cases.

Results: A 52-year-old patient with XLMC and cataracts underwent bilateral clear corneal phacoemulsification, capsule tension ring (CTR) insertion, and in the bag intraocular lens (IOL) implantation. Two years after the procedure the IOL remained centrally located and stable in both eyes. In the postoperative refraction, the patient had a large hyperopic refractive error in the right eye, and a moderate hyperopic refractive error in the left eye. A similar pattern was observed in previously reported cases. Pooling all cases together we observed that the Holladay II formula produced more accurate IOL power calculations than the SRK-T formula. Still, both formulas diverged from the ideal IOL power by approximately 1 diopter per mm of axial length in subjects with axial lengths larger than 24?mm.

Conclusion: Axial length seems to be the main source of IOL power calculation error in XLMC patients. Compared to SRK-T the Holladay II formula provides better refractive results, yet both formulas may require further adjustment depending on the axial length.     

A Novel CYP1B1 Mutation with Congenital Glaucoma and Total Aniridia

Purpose: Primary congenital glaucoma is a common disorder in the Middle East mainly caused by mutations in the the CYP1Bl gene. We report a family with three siblings that presented with recalcitrant childhood glaucoma, aniridia in two siblings with a novel CYP1B1 gene mutation.

Materials and methods: Review of pedigree, clinical history and clinical course of the family. Genetic testing in the affected family members.

Results: Three sisters presented with clinical findings of severe congenital glaucoma and a positive family history. Clinical examination of two of sisters revealed corneal scarring, bilateral aniridia with severe glaucoma that required multiple surgical procedures to control intraocular pressure. The third sibling presented with garden-variety primary congenital glaucoma. Genetic analysis revealed a novel CYP1B1 gene mutation (g.8291 C?>?T; p.S485F).

Conclusion: CYP1B1 mutation related congenital glaucoma can present with an extreme form of anterior segment dysgenesis that includes recalcitrant glaucoma, corneal opacification and aniridia.     

CYP1B1 Mutations are a Major Contributor to Juvenile-Onset Open Angle Glaucoma in Saudi Arabia

To describe the genotype and phenotype in 14 unrelated Saudis with juvenile open angle glaucoma (JOAG). Detailed clinical examination was carried out and we sequenced cytochrome P450, family 1, subfamily B (CYP1B1), Myocilin (MYOC) and latent-transforming growth factor beta-binding protein 2 (LTBP2) genes. Twelve (85.7%) patients had apparent sporadic inheritance and 2 (14.3%) presented with a family history of glaucoma. Overall, 12 patients (85.7%) had CYP1B1 mutation. Nine patients had CYP1B1 mutations in a homozygous status. Eight of these had homozygous p.G61E mutation and one had a silent (no amino acid change) sequence change. Two patients had p.G61E mutation in a compound heterozygous status with another CYP1B1 mutation (p.L432V). Two patients had p.G61E in a heterozygous status with no other mutation, while one patient had no mutation(s). None of the patients had any mutation(s) in the MYOC or LTBP2 genes. JOAG associated with CYP1B1 mutations occurs at a high rate in the Saudi population. A specific genotype-phenotype relationship was not demonstrated.     

结晶样视网膜色素变性中与CYP4V2基因相关的致病突变

目的：使用Sanger测序法鉴定2个中国结晶样视网膜色素变性(BCD)家系中CYP4V2基因的突变位点。

方法：收集2019-01/09临床诊断为BCD患者的临床相关资料。采集患者、患者家系成员的外周血,提取DNA,利用Sanger测序法鉴定突变位点。

结果：共收集2个BCD先证者,先证者均表现为渐进性视力下降,眼底均可见典型的结晶样物质沉积。测序发现先证者1及其患病的哥哥,妹妹均在CYP4V2基因上存在c.802-8_810del17insGC的纯合突变。而先证者2则在CYP4V2基因上存在c.219T>A(p.F73L)、c.802-8_810del17insGC杂合突变。

结论： 中国BCD患者中最常见的c.802-8_810del17insGC突变在先证者1家系中为纯合突变,是其家系的致病突变。而先证者2则携带了中国BCD患者最常见的c.802-8_810del17insGC杂合突变,同时先证者2还携带c.219T>A(p.F73L)错义突变,突变均影响了CYP4V2基因的正常编码,进而导致疾病。     

A Case of 22q11.2 Deletion Syndrome with Peters Anomaly,Congenital Glaucoma,and Heterozygous Mutation in CYP1B1

We read with interest the recent publication by Tarlan and colleagues1 Tarlan B, Kiratli H, Kilic E, et al. A case of 22q11.2 deletion syndrome with right microphthalmia and left corneal staphyloma. Ophthalmic Genet 2013; [Epub ahead of print][PubMed], [Web of Science ®] , [Google Scholar] describing a patient with 22q11.2 deletion syndrome and ocular features of right microphthalmia and left anterior segment dysgenesis. While anterior segment dysgenesis disorders are occasionally reported with 22q11.2 deletions,2–5 Casteels I, Devriendt K. Unilateral Peters’ anomaly in a patient with DiGeorge syndrome. J Pediatr Ophthalmol Strabismus 2005;42:311–313 Binenbaum G, McDonald-McGinn DM, Zackai EH, et al. Sclerocornea associated with the chromosome 22q11.2 deletion syndrome. Am J Med Genet A 2008;146:904–909 Casteels I, Casaer P, Gewillig M, et al. Ocular findings in children with a microdeletion in chromosome 22q11.2. Eur J Pediatr 2008;167:751–755 Erdogan MK, Utine GE, Alanay Y, Aktas D. Unilateral Peters’ anomaly in an infant with 22q11.2 deletion syndrome. Clin Dysmorphol 2008;17:289–290  this remains a rare association. We report here an 8-year-old patient with 22q11.2 deletion syndrome and bilateral Peters anomaly with congenital glaucoma; in addition, our patient was found to have a single heterozygous mutation in CYP1B1, c.83C?>?T, p.(Ser28Trp).     

Genotype and phenotype correlations in congenital glaucoma: CYP1B1 mutations, goniodysgenesis, and clinical characteristics

PURPOSE: To determine whether there is a correlation among mutations in the cytochrome P4501B1 gene (CYP1B1), the degree of angle dysgenesis observed histologically, and disease severity in congenital glaucoma. DESIGN: Interventional case series. METHODS: Direct DNA sequencing was used to screen six unrelated children with congenital glaucoma, each set of parents, and all siblings for CYP1B1 mutations. Specimens of the anterior chamber angle obtained at trabeculectomy were examined histologically to identify abnormalities of the aqueous outflow pathway. CYP1B1 mutations were correlated with both the degree of angle dysgenesis and the patients' disease severity (age at diagnosis, difficulty in achieving intraocular pressure [IOP]) control. RESULTS: Four (66.7%) of the six patients were compound heterozygotes for mutations in the CYP1B1 gene. Seven of the eight CYP1B1 mutations were identified, including two novel mutations (R117P, C209R) and five others previously described (G61E, R368H, R390H, E229K, 4340delG). The cases were divided on the basis of histological phenotype into categories of (1) severe goniodysgenesis highlighted by the agenesis of the canal of Schlemm (two patients), (2) moderate goniodysgenesis characterized by the presence of a band of collagenous tissue (CT) in the trabecular meshwork (TM) and/or the juxtacanalicular tissues (JXT) (three patients), and (3) mild goniodysgenesis with deposition of a mucopolysaccharide material in the JXT (one patient). CYP1B1 mutations were identified in both cases of severe angle dysgenesis and two of three cases of moderate dysgenesis. Disease severity closely correlated with the degree of angle dysgenesis. CONCLUSIONS: Most patients in our cohort had compound heterozygous CYP1B1 mutations. Specific CYP1B1 mutations may be associated with severe or moderate angle abnormalities.