Predictive genetic testing in minors for Myocilin juvenile onset open angle glaucoma

Author manuscript made available following 12 month embargo from date of publication (28 Jan 2015) in accordance with publisher copyright policy.Myocilin glaucoma is an autosomal dominant disorder leading to irreversible blindness, but early intervention can minimize vision loss and delay disease progression. The purpose of this study was to discuss the benefits of predictive genetic testing in minors for Myocilin mutations associated with childhood onset glaucoma. Three families with Myocilin mutations associated with an age of onset before 18 years and six unaffected at-risk children were identified. Predictive genetic testing was discussed with the parents and offered for at-risk minors. Parents opted for genetic testing in half of the cases. None carried the familial mutation. The age of disease onset in the family, the severity of the condition, and the age of the child are all factors that appear to influence the decision of the parent to test their children. Predictive genetic testing for early onset Myocilin glaucoma can facilitate early detection of disease or discharge from routine ophthalmic examinations

Profiling of WDR36 Missense Variants in German Patients with Glaucoma

PURPOSE. Mutations in WDR36 were recently reported in patients with adult-onset primary open-angle glaucoma (POAG). In this study, the prevalence of WDR36 variants was investigated in patients with glaucoma who were of German descent with diverse age of onset and intraocular pressure levels. METHODS. Recruited were 399 unrelated patients with glaucoma and 376 healthy subjects of comparable age and origin, who had had repeated normal findings in ophthalmic examinations. The frequency of observed variants was obtained by direct sequencing of the entire WDR36 coding region. RESULTS. A total of 44 WDR36 allelic variants were detected, including 14 nonsynonymous amino acid alterations, of which 7 are novel (P31T, Y97C, D126N, T403A, H411Y, H411L, and P487R) and 7 have been reported (L25P, D33E, A163V, H212P, A449T, D658G and I264V). Of these 14 variants, 6 were classified as polymorphisms as they were detected in patients and control individuals at similar frequencies. Eight variants present in 15 patients (3.7%) but only 1 control individual (0.2%) were defined as putative disease-causing variants (P 0.0005). Within this patient group, 12 (80%) presented with high and 3 (20%) with low intraocular pressure. Disease severity and age of onset showed a broad range. CONCLUSIONS. The occurrence of several rare putative diseasecausing variants in patients with glaucoma suggests that WDR36 may be a minor disease-causing gene in glaucoma, at least in the German population. The large variability in WDR36, though, requires functional validation of these variants, once its function is characterized.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM)UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biologí

Heterozygous Loss-of-Function Variants in CYP1B1 Predispose to Primary Open-Angle Glaucoma

Purpose.: Although primary congenital glaucoma (PCG)–associated CYP1B1 mutations in the heterozygous state have been evaluated for association with primary open-angle glaucoma (POAG) in several small studies, their contribution to the occurrence of POAG is still controversial. The present study was conducted to determine whether heterozygous functionally characterized CYP1B1 mutations are associated with the disease in a large cohort of German patients with POAG. Methods.: The frequency of CYP1B1 variants on direct sequencing of the entire coding region was compared in 399 unrelated German patients with POAG (270, POAG; 47, JOAG; and 82, NTG) and 376 control subjects without any signs of glaucoma on ophthalmic examination. In vitro functional assays were performed and relative enzymatic activity of the CYP1B1 variants embedded in their respective background haplotypes and not previously unambiguously classified were determined, to assess their possible causative role. Results.: Apart from known polymorphic variants, 11 amino acid substitutions in CYP1B1 reported before, both in PCG and POAG cases, were identified. After in vitro functional assay, variants P52L and R368H showed marked reduction of activity, confirming their role as loss-of-function mutations similar to previously determined variants G61E, N203S, and G329V. In contrast, variants G168D, A443G, and A465V showed no relevant effects and were thus classified as polymorphisms. Overall, seven functionally impaired variants were present in 13 (3.6%) patients and in 1 (0.2%) control subject (P = 0.002, OR = 5.4). Reanalysis of previous studies reporting CYP1B1 mutations in patients with POAG based on updated functional validation showed a significant excess of carriers among patients compared to controls (OR = 3.85; P = 2.3 × 10−7). Conclusions.: Heterozygous CYP1B1 mutations with absent or reduced relative enzymatic activity can be considered a risk factor for POAG.German Research Foundation/[WE1259/14-3]/DFG/GermanyGerman Research Foundation/[SFB-539]/DFG/GermanyUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM

Primary Congenital Glaucoma: A Novel Single-Nucleotide Deletion and Varying Phenotypic Expression for the 1546-1555dup Mutation in the GLC3A (CYP1B1) Gene in 2 Families of Different Ethnic Origin

Artículo científico -- Universidad de Costa Rica, Instituto de Investigaciones en Salud. 2003. Este documento es privado debido a limitaciones de derechos de autor.Purpose: To present new molecular genetic data on primary congenital glaucoma from 2 families, 1 isolated case and 3 familial cases due to mutations in the cytochrome P-450 1B1 (CYP1B1) gene. Methods: All diagnoses were made by slit-lamp biomicroscopy, gonioscopy, cornea and optic disk measurements, ultrasound-biometry, and automated static threshold perimetry where possible. Mutation screening was performed by direct sequence analysis of DNA extracted from peripheral blood of the patients and their relatives. Results: For the isolated case, a child of 4 years, a homozygous nucleotide deletion within a tetrad of cytosines (nt622–625, 622delC) was found leading to a predicted nonsense codon 93 truncating the protein by 450 amino acids. For the familial cases, the 3 affected members showed a homozygous mutation 1546–1555dupTCATGCCACC for which 9 healthy relatives proved to be heterozygous. The phenotypic expression of these 3 patients varied widely. Conclusion: Our results confirm the crucial role of CYP1B1 mutations for congenital glaucoma.Universidad de Costa Rica. Instituto de Investigaciones en SaludUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

Heterozygous Loss-of-Function Variants in CYP1B1 Predispose to Primary Open-Angle Glaucoma

PURPOSE. Although primary congenital glaucoma (PCG)-associated CYP1B1 mutations in the heterozygous state have been evaluated for association with primary open-angle glaucoma (POAG) in several small studies, their contribution to the occurrence of POAG is still controversial. The present study was conducted to determine whether heterozygous functionally characterized CYP1B1 mutations are associated with the disease in a large cohort of German patients with POAG. METHODS. The frequency of CYP1B1 variants on direct sequencing of the entire coding region was compared in 399 unrelated German patients with POAG (270, POAG; 47, JOAG; and 82, NTG) and 376 control subjects without any signs of glaucoma on ophthalmic examination. In vitro functional assays were performed and relative enzymatic activity of the CYP1B1 variants embedded in their respective background haplotypes and not previously unambiguously classified were determined, to assess their possible causative role. RESULTS. Apart from known polymorphic variants, 11 amino acid substitutions in CYP1B1 reported before, both in PCG and POAG cases, were identified. After in vitro functional assay, variants P52L and R368H showed marked reduction of activity, confirming their role as loss-of-function mutations similar to previously determined variants G61E, N203S, and G329V. In contrast, variants G168D, A443G, and A465V showed no relevant effects and were thus classified as polymorphisms. Overall, seven functionally impaired variants were present in 13 (3.6%) patients and in 1 (0.2%) control subject (P ϭ 0.002, OR ϭ 5.4). Reanalysis of previous studies reporting CYP1B1 mutations in patients with POAG based on updated functional validation showed a significant excess of carriers among patients compared to controls (OR ϭ 3.85; P ϭ 2.3 ϫ 10 Ϫ7 ). CONCLUSIONS. Heterozygous CYP1B1 mutations with absent or reduced relative enzymatic activity can be considered a risk factor for POAG. (Invest Ophthalmol Vis Sci. 2010;51: 249 -254

Novel Mutations in the MYOC/GLC1A Gene in a Large Group of Glaucoma Patients

Artículo científico -- Universidad de Costa Rica. Instituto de Investigaciones en Salud, 2002. Por políticas de la revista en la que el artículo fue publicado no es posible descargar la versión del editor/PDF; no obstante, se pone a disposición el enlace de la publicación original.Mutations at the myocflin (MYOC) gene within the GLC1A locus have been revealed in 2- 4% of patients suffering primary open angle glaucoma (POAG) worldwide. In our ongoing glaucoma study sixhundred eighty two persons have been screend for MYOC mutations. The first group consisted of 453 patients from a long-term clinical study diagnosed either with juvenile OAG (JOAG), POAG, ocular hypertension (OHT) or normal tension glaucoma (NTG) plus 22 cases of secondary glaucoma. This group, and additional 83 healthy controls, is part of a long term study with repeated clinical examinations at the University of Erlangen-Nurnberg. An additional sample of 124 glaucoma patients or at risk persons referred from other sources were included in the mutation screening. Five novel mutations, namely Gly434Ser, Asn450Asp, Va1251Ala, 11e345Met and Ser393Asn, could he identified as cause of preperimetrk POAG, JOAG, normal tension POAG and POAG. Myocilln mutations were identified similar with previous reports with other ethnic populations at the rate of 11/341 (3.2%) probandsUniversidad de Costa Rica. Instituto de Investigaciones en SaludUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

Prevalence of CYP1B1 mutations in Australian patients with primary congenital glaucoma

Analysis of CYP1B1 in primary congenital glaucoma (PCG) patients from various ethnic populations indicates that allelic heterogeneity is high, and some mutations are population specific. No study has previously reported the rate or spectrum of CYP1B1 mutations in Australian PCG patients. The aim of this study is to determine the frequency of CYP1B1 mutations in our predominately Caucasian, Australian cohort of PCG cases. Thirty-seven probands were recruited from South-Eastern Australia, along with 100 normal control subjects. Genomic DNA was extracted and the coding regions of CYP1B1 analysed by direct sequencing. Sequence analysis identified 10 different CYP1B1 disease-causing variants in eight probands (21.6%). Five subjects were compound heterozygotes, two subjects heterozygous and one homozygous for CYP1B1 mutations. Three missense mutations are novel (D192Y, G329D, and P400S). None of the novel mutations identified were found in normal controls. One normal control subject was heterozygous for the previously reported CYP1B1 R368H mutation. Six previously described probable polymorphisms were also identified. Mutations in CYP1B1 account for approximately one in five PCG cases from Australia. Our data also supported the high degree of allelic heterogeneity seen in similar studies from other ethnic populations, thereby underscoring the fact that other PCG-related genes remain to be identified