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Primary open-angle glaucoma (POAG) is a complex disease with a strong hereditably component. Several genetic variants have recently been associated with POAG, partially due to technological improvements such as next-generation sequencing (NGS). The aim of this study was to genetically analyze patients with POAG to determine the contribution of rare variants and hypomorphic alleles associated with glaucoma as a future method of diagnosis and early treatment. Seventy-two genes potentially associated with adult glaucoma were studied in 61 patients with POAG. Additionally, we sequenced the coding sequence of CYP1B1 gene in 13 independent patients to deep analyze the potential association of hypomorphic CYP1B1 alleles in the pathogenesis of POAG. We detected nine rare variants in 16% of POAG patients studied by NGS. Those rare variants are located in CYP1B1, SIX6, CARD10, MFN1, OPTC, OPTN, and WDR36 glaucoma-related genes. Hypomorphic variants in CYP1B1 and SIX6 genes have been identified in 8% of the total POAG patient assessed. Our findings suggest that NGS could be a valuable tool to clarify the impact of genetic component on adult glaucoma. However, in order to demonstrate the contribution of these rare variants and hypomorphic alleles to glaucoma, segregation and functional studies would be necessary. The identification of new variants and hypomorphic alleles in glaucoma patients will help to configure the genetic identity of these patients, in order to make an early and precise molecular diagnosis. [ABSTRACT FROM AUTHOR]

Glaucoma is a blinding disease that can occur at all ages, with Mendelian inheritance typical for the rare early onset disease (before age 40) and complex inheritance evident in common adult‐onset forms of disease. Genetic and genomic studies, including genome‐wide association studies (GWAS) have identified new genetic variants contributing to glaucoma in the last years. Genes correlating with glaucoma risk may involve: ocular development, intraocular pressure, trabecular meshwork function or some of them are directly related to optic nerve susceptibility such as retinal ganglion cell membranes, mitochondrial function, reactive oxygen species production and management, and mechanisms controlling apoptosis. These findings are providing new insights into the underlying molecular mechanisms responsible for glaucoma that could eventually lead to novel gene‐based therapies, including strategies for neuroprotection. We present our study about the genetic analysis of a cohort of Spanish patients with primary open‐angle glaucoma to determine the contribution of rare variants associated with this disease through next generation sequencing (NGS) glaucoma gene panel, as a future method of diagnosis and early treatment. We found some rare variants associated with optic disk parameters and function in some families with high and normal tension glaucoma with allelic frequencies significantly higher than the frequency in the general population by NGS. Those rare variants are located in SIX6, CARD10, MFN1, OPTN, and WDR36 glaucoma‐related genes. These risk variants have been associated to the alteration of retinal ganglion cells through different mechanisms, thereby increasing the risk of glaucoma‐associated vision loss. The discovery of new genetic variants associated with augmented susceptibility of the optic nerve may in the future open the door to designing new neuroprotection gene therapies aimed at repairing damaged genes or providing them through different vectors. [ABSTRACT FROM AUTHOR]

Purpose: Here we present two siblings with combined cilioretinal artery and vein occlusion (CLARVO), with genetic confirmation of glaucoma as the underlying etiology and discovering of two novel variants of CARD10 and OLFM2. Methods: Ancillary tests were performed to rule out other etiologies, and genetic tests using next generation sequencing (NGS) were performed in the two siblings. An extensive literature research was performed of similar cases of CLARVO and glaucoma, as well as the genetics (NCBI Genes Database) found in our patients. Results: In April 2016, a 39‐years‐old man and a 45‐year‐old woman came to the Emergency Room referring visual loss on their right eye, also both with an onset of the symptoms differing only two weeks. They denied any abnormalities, recent travels or drugs abuse. On the examination, both presented CLARVO in the right eye, a more severe condition in the female patient along with lower visual acuity. Both patients showed a pigmentary dispersion glaucoma with a higher cup‐to‐disc ratio in their right eye. IOP was controlled with medical treatment, and in the female peripheral iridotomies and selective trabeculoplasty were also needed. A genetic analysis with NGS showed variants of CARD10 (pThr436Met) in both siblings, and in OLFM2 (p.ARg460=) in the female. These genes have been related to a higher risk of increased IOP (CARD10) and normal development of the structures of the eye (OLFM2). Also, OLFM2 has been recently linked to vascular smooth muscle cells regulation. Conclusions: CLARVO is a rare entity. As in other vascular retinal diseases, like in retinal vein occlusion, even in younger patients, classic predisposing factors like glaucoma should be considered. When available, genetic tests should be performed, especially in presumed familiar association. The combination of the genetic variants in our patients could be related to both a higher predisposition of high‐pressure glaucoma, along with an increased susceptibility of the retinal vasculature; however, further research is needed to confirm this association between CLARVO and glaucoma. [ABSTRACT FROM AUTHOR]