Risk factors for incident open-angle glaucoma: the Barbados Eye Studies.

Genetic and genomic studies, including genome-wide association studies (GWAS) have accelerated the discovery of genes contributing to glaucoma, the leading cause of irreversible blindness world-wide. Glaucoma 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. Recent studies have suggested possible therapeutic targets for some patients with early-onset glaucoma based on the molecular and cellular events caused by MYOC, OPTN and TBK1 mutations. Diagnostic genetic tests using early-onset glaucoma genes are also proving useful for pre-symptomatic disease detection and genetic counseling. Recent GWAS completed for three types of common adult-onset glaucoma have identified novel loci for POAG (primary-open-angle glaucoma) (ABCA1, AFAP1, GMDS, PMM2, TGFBR3, FNDC3B, ARHGEF12, GAS7, FOXC1, ATXN2, TXNRD2); PACG (primary angle-closure glaucoma (EPDR1, CHAT, GLIS3, FERMT2, DPM2-FAM102); and exfoliation syndrome (XFS) glaucoma (CACNA1A). In total sixteen genomic regions have been associated with POAG (including the normal tension glaucoma (NTG) subgroup), 8 with PACG and 2 with XFS. These studies are defining important biological pathways and processes that contribute to disease pathogenesis.

Genetics of glaucoma.

Glaucoma can be inherited as a mendelian autosomal-dominant or autosomal-recessive trait, or as a complex multifactorial trait. Genetic approaches have helped define the underlying molecular events responsible for some mendelian forms of the disease and have identified the chromosome locations of genes that are likely to contribute to common complex forms. Future directions include the discovery of new glaucoma genes, determining the clinical phenotypes associated with specific genes and mutations, investigating environmental factors that may contribute to the disease, investigating gene-environment interactions and gene-gene interactions, and developing a mutation database that can be used for diagnostic and prognostic testing.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/418994/esa60009_30_37.pdf

Genetic Etiologies of Glaucoma

Usher syndrome (USH) comprises a group of autosomal recessively inherited disorders characterized by a dual sensory impairment of the audiovestibular and visual systems. Three major clinical subtypes (USH type I, USH type II and USH type III) are distinguished on the basis of the severity of the hearing loss, the presence or absence of vestibular dysfunction and the age of onset of retinitis pigmentosa (RP). Since the cloning of the first USH gene (MYO7A) in 1995, there have been remarkable advances in elucidating the genetic basis for this disorder, as evidence for 11 distinct loci have been obtained and genes for 9 of them have been identified. The USH genes encode proteins of different classes and families, including motor proteins, scaffold proteins, cell adhesion molecules and transmembrane receptor proteins. Extensive information has emerged from mouse models and molecular studies regarding pathogenesis of this disorder and the wide phenotypic variation in both audiovestibular and/or visual function. A unifying hypothesis is that the USH proteins are integrated into a protein network that regulates hair bundle morphogenesis in the inner ear. This review addresses genetics and pathological mechanisms of USH. Understanding the molecular basis of phenotypic variation and pathogenesis of USH is important toward discovery of new molecular targets for diagnosis, prevention and treatment of this debilitating disorder.

/pdf/genetics-and-pathological-mechanisms-of-usher-syndrome-5cisq9k3tl.pdf

Genetics and pathological mechanisms of Usher syndrome

Gene mapping for primary open angle glaucoma.

.


Purpose: Usher syndrome types I and II are clinical syndromes with substantial genetic and clinical heterogeneity. We undertook the current study in order to identify ocular symptoms and signs that could differentiate between the two types.



Methods:  Sixty-seven patients with Usher syndrome were evaluated. Based on audiologic and vestibular findings, patients were classified as either Usher type I or II. The severity of the ocular signs and symptoms present in each type were compared.



Results:  Visual acuity, visual field area, electroretinographic amplitude, incidence of cataract and macular lesions were not significantly different between Usher types I and II. However, the ages when night blindness was perceived and retinitis pigmentosa was diagnosed differed significantly between the two types.



Conclusions:  There seems to be some overlap between types I and II of Usher syndrome in regard to the ophthalmologic findings. However, night blindness appears earlier in Usher type I (although the difference in age of appearance appears to be less dramatic than previously assumed). Molecular elucidation of Usher syndrome may serve as a key to understanding these differences and, perhaps, provide a better tool for use in clinical diagnosis, prognosis and genetic counseling.

https://onlinelibrary.wiley.com/doi/pdf/10.1034/j.1600-0420.2002.800215.x

Usher syndrome clinical types I and II: could ocular symptoms and signs differentiate between the two types?

Primary open-angle glaucoma (POAG) is characterized by damage to the optic nerve with associated loss of vision. Six named genetic loci have been identified as contributing to POAG susceptibility by genetic linkage analysis of mostly Caucasian families, and two of the six causative genes have been identified. The Barbados Family Study of Open-Angle Glaucoma (BFSG) was designed to evaluate the genetic component of POAG in a population of African descent. A genome-wide scan was performed on 1327 individuals from 146 families in Barbados, West Indies. Linkage results were based on models and parameter estimates derived from a segregation analysis of these families, and on model-free analyses. Two-point LOD scores >1.0 were identified on chromosomes 1, 2, 9, 10, 11, and 14, with increased multipoint LOD scores being found on chromosomes 2, 10, and 14. Fine mapping was subsequently carried out and indicated that POAG may be linked to intervals on chromosome 2q between D2S2188 and D2S2178 and chromosome 10p between D10S1477 and D10S601. Heterogeneity testing strongly supports linkage for glaucoma to at least one of these regions and suggests possible linkages to both. Although TIGR/myocilin and optineurin mutations have been shown to be causally linked to POAG in other populations, findings from this study do not support either of these as causative genes in an Afro-Caribbean population known to have relatively high rates of POAG.

A genome-wide scan for primary open-angle glaucoma (POAG): the Barbados Family Study of Open-Angle Glaucoma

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Usher syndrome clinical types I and II: could ocular symptoms and signs differentiate between the two types?

A genome-wide scan for primary open-angle glaucoma (POAG): the Barbados Family Study of Open-Angle Glaucoma