A novel de novo Myocilin variant in a patient with sporadic juvenile open angle glaucoma

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Glaucoma is a leading cause of irreversible blindness. Pathogenic variants in the Myocilin gene (MYOC) cause juvenile open angle glaucoma (JOAG) in 8-36% of cases, and display an autosomal dominant inheritance with high penetrance. Molecular diagnosis is important for early identification as therapies are effective in minimizing vision loss and MYOC variants can be associated to severe glaucoma. MYOC variants are usually inherited, however a fifth of carriers do not report a family history. The occurrence of de novo MYOC variants is currently unknown. CASE PRESENTATION: In this study we investigated a 14 year old male Caucasian patient diagnosed with JOAG, and no family history of glaucoma. A novel probably deleterious MYOC:p.(Pro254Leu) variant was identified in the index case. This variant was not present in the parents or the siblings. CONCLUSION: This is the second report of a de novo MYOC variant in a sporadic case of JOAG and it is currently unknown if this mechanism occurs more frequently. This finding emphasizes the importance of screening individuals with JOAG for MYOC mutations irrespective of a negative family history

Primary congenital glaucoma due to paternal uniparental isodisomy of chromosome 2 and CYP1B1 deletion

© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Background: CYP1B1 variants and deletions are the most common cause of primary congenital glaucoma (PCG). Methods: We investigated an individual with PCG from the Australian and New Zealand Registry of Advanced Glaucoma. We performed sequencing of the CYP1B1 gene, followed by Multiplex Ligation-dependent Probe Amplification and SNP array. Results: We identified a homozygous deletion of the CYP1B1 gene by Multiplex Ligation-dependent Probe Amplification and confirmed that the father was heterozygous for a CYP1B1 deletion but the mother had normal gene copy number. SNP array identified paternal uniparental isodisomy of the entire chromosome 2. Conclusions: This study is the first report of a homozygous CYP1B1 whole gene deletion due to paternal uniparental isodisomy of chromosome 2 as a cause of PCG. These results illustrate the importance of genetic testing in providing appropriate genetic counseling regarding the risks of recurrence

Compound heterozygote myocilin mutations in a pedigree with high prevalence of primary open-angle glaucoma

This article is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 3.0, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license.Purpose: To describe the phenotype of ocular hypertension and primary open-angle glaucoma in a family with individuals compound heterozygote for Gln368STOP and Thr377Met myocilin (MYOC) mutations. Methods: Family members of the proband underwent comprehensive ocular clinical examination and DNA sequencing for MYOC mutations. Results: A 34-year-old woman with marked ocular hypertension was found to carry Gln368STOP and Thr377Met MYOC mutations. Three other siblings carried both mutations, while one carried Gln368STOP alone. Three of five siblings had received treatment for ocular hypertension or early glaucoma, with the average age of diagnosis 28 years; one required trabeculectomy at age 27. The mother of the proband was found to be a carrier for Gln368STOP alone, which indicates that her offspring with both Gln368STOP and Thr377Met carry variants on opposing alleles. Conclusions: This pedigree is the first report with individuals compound heterozygote for the two most common glaucoma-causing MYOC variants. The combination of mutations manifests a more severe phenotype than either alone. Identification of gene changes associated with glaucoma within the family has enabled unaffected members to stratify their risk of future disease and institute closer monitoring and early treatment.CERA receives Operational Infrastructure Support from the Victorian Government. The Australian and New Zealand Registry of Advanced Glaucoma is funded by the RANZCO Eye Foundation. KPB and JEC are funded by a Career Development Award and Practitioner Fellowship from the National Health and Medical Research Council of Australia, respectively

CYP1B1 copy number variation is not a major contributor to primary congenital glaucoma

This article is published under a Creative Commons Attribution-NonCommercial-NoDerivatives License 3.0, or CC BY-NC-ND 3.0 (see http://creativecommons.org/licenses/by-nc-nd/3.0/ for license terms). The authors retain copyright and grant Molecular Vision an irrevocable, royalty-free, perpetual license to publish and distribute the article, in all formats now known or later developed, and to identify Molecular Vision as the original publisher.Purpose: To evaluate the prevalence and the diagnostic utility of testing for CYP1B1 copy number variation (CNV) in primary congenital glaucoma (PCG) cases unexplained by CYP1B1 point mutations in The Australian and New Zealand Registry of Advanced Glaucoma. Methods: In total, 50 PCG cases either heterozygous for disease-causing variants or with no CYP1B1 sequence variants were included in the study. CYP1B1 CNV was analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA). Results: No deletions or duplications were found in any of the cases. Conclusion: This is the first study to report on CYP1B1 CNV in PCG cases. Our findings show that this mechanism is not a major contributor to the phenotype and is of limited diagnostic utility

Autosomal dominant nanophthalmos and high hyperopia associated with a C-terminal frameshift variant in MYRF

Made available with a Creative Commons Attribution-NonCommercial-NoDerivatives License 3.0, or CC BY-NC-ND 3.0 (see http://creativecommons.org/licenses/by-nc-nd/3.0/ for license terms). Copyright (2019) The authors.Purpose: Nanophthalmos is a rare subtype of microphthalmia associated with high hyperopia and an increased risk of angle-closure glaucoma. We investigated the genetic cause of nanophthalmos and high hyperopia in an autosomal dominant kindred. Methods: A proband with short axial length, high hyperopia, and dextrocardia was subjected to exome sequencing. Human and rodent gene expression data sets were used to investigate the expression of relevant genes. Results: We identified a segregating heterozygous frameshift variant at the 3′ end of the penultimate exon of MYRF. Using Myc-MYRF chromatin immunoprecipitation data from rat oligodendrocytes, MYRF was found to bind immediately upstream of the transcriptional start site of Tmem98, a gene that itself has been implicated in autosomal dominant nanophthalmos. MYRF and TMEM98 were found to be expressed in the human retina, with a similar pattern of expression across several dissected human eye tissues. Conclusions: C-terminal variants in MYRF, which are expected to escape nonsense-mediated decay, represent a rare cause of autosomal dominant nanophthalmos with or without dextrocardia or congenital diaphragmatic hernia

Biallelic CPAMD8 Variants Are a Frequent Cause of Childhood and Juvenile Open-Angle Glaucoma

© 2020 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND licensePurpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Design Retrospective, multicenter case series. Participants A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. Purpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Methods Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. Main Outcome Measures Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. Results We identified rare (allele frequency < 4×10−5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest–derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. Conclusions Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment

Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma Leads to Early Identification of At-Risk Individuals.

This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/. Following 12 month embargo from date of publication (16 Dec 2016

Genome-wide association identifies ATOH7 as a major gene determining human optic disc size

Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P = 6.2 × 10−10, near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P = 3.4 × 10−10. Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P = 1.3 × 10−10 to 4.3 × 10−11, top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P = 1.5 × 10−7, in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P = 0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups