Retinal phenotypic characterization of patients with ABCA4 retinopathydue to the homozygous p.Ala1773Val mutation.

Purpose: To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4. Methods: Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient. Results: Best-corrected visual acuities ranged from 20/200 to 4/200. The median age of the patients at diagnosis was 23.3 years. The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). An atypical retinal pigmentation pattern was observed in the patients, and the majority showed cone-rod dystrophy on full-field ERG. In vivo retinal microstructure assessment with OCT demonstrated central retinal thinning, variable loss of photoreceptors, and three different patterns of structural retinal degeneration. Two dissimilar patterns of abnormal autofluorescence were observed. No apparent age-related differences in the pattern of retinal degeneration were observed. Conclusions: The results indicate that this particular mutation in ABCA4 is associated with a severe retinal phenotype and thus, could be classified as null. Careful phenotyping of patients carrying specific mutations in ABCA4 is essential to enhance our understanding of disease expression linked to particular mutations and the resulting genotype-phenotype correlations.

Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations.

Tietz syndrome and Waardenburg syndrome type 2A are allelic conditions caused by MITF mutations. Tietz syndrome is inherited in an autosomal dominant pattern and is characterized by congenital deafness and generalized skin, hair, and eye hypopigmentation, while Waardenburg syndrome type 2A typically includes variable degrees of sensorineural hearing loss and patches of de-pigmented skin, hair, and irides. In this paper, we report two unrelated families with MITF mutations. The first family showed an autosomal dominant pattern and variable expressivity. The second patient was isolated. MITF gene analysis in the first family demonstrated a c.648A>C heterozygous mutation in exon 8 c.648A>C; p. (R216S), while in the isolated patient, an apparently de novo heterozygous c.1183_1184insG truncating mutation was demonstrated in exon 10. All patients except one had bilateral reduced ocular anteroposterior axial length and a high hyperopic refractive error corresponding to posterior microphthalmos, features that have not been described as part of the disease. Our results suggest that posterior microphthalmos might be part of the clinical characteristics of Tietz/Waardenburg syndrome type 2A and expand both the clinical and molecular spectrum of the disease. © 2016 Wiley Periodicals, Inc.

The T allele of lysyl oxidase-like 1 rs41435250 is a novel risk factor for pseudoexfoliation syndrome and pseudoexfoliation glaucoma independently and through intragenic epistatic interaction.

PURPOSE: Two coding single nucleotide polymorphisms (SNPs) in lysyl oxidase-like 1 (LOXL1) are major genetic risk factors for pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG) in diverse populations. However, recent conflicting results suggest that the currently known disease-associated missense variants R141L and G153D are not causal and that they may be proxies for other unknown functional LOXL1 variants. The purpose of this study was to investigate the possible association of XFS/XFG with a novel LOXL1 exonic variant. METHODS: Genotypes of the synonymous coding LOXL1 SNP rs41435250 (p.A310A) were identified with direct sequencing. A case-control study was conducted with 115 unrelated Mexican patients with XFS/XFG (43 XFS/72 XFG) as well as 130 control subjects. Allele frequencies, genotype frequencies, and Hardy-Weinberg equilibrium were assessed with the HaploView software. A probable intragenic epistasis effect was assessed by comparing the frequencies of the rs41435250 alleles among a subset of 51 patients with XFS/XFG without the high-risk TT genotype at LOXL1 intronic rs2165241 and the control group. RESULTS: The T allele of the exonic SNP rs41435250 was more frequent in patients with XFS/XFG than in controls (odds ratios [95% confidence intervals] = 2.0 [1.1-3.6]; p = 0.01). Interestingly, the strength of association with the rs41435250 T allele was strongly increased (odds ratio [95% confidence intervals] = 4.9 [2.7-9.1]; p = 0.00000005) in the subgroup of subjects without the risk genotype at rs2165241. CONCLUSIONS: Our results indicate that allele T of rs41435250 is a novel risk genetic factor for XFS/XFG development in our population and points toward the possibility of a LOXL1 intragenic epistatic effect between rs41435250 and rs2165241. Functional studies are needed to investigate if the synonymous p.A310A mutation could affect messenger ribonucleic acid stability and thus LOXL1 enzymatic activity.

Association study of multiple gene polymorphisms with the risk of adult-onset primary open-angle glaucoma in a Mexican population.

The aim of this study was to investigate the association of multiple primary open-angle glaucoma (POAG)-risk alleles in a Mexican population for the first time. Genotyping was performed for a total of 26 previously associated alleles located in 11 different genes, including MYOC, CYP1B1, OPTN, IL1A, TNF, OPA1, EDNRA, AGTR2, MTHFR, GSTM1, and GSTT1. The frequencies of these variants were compared in a group of 218 individuals (118 with POAG and 100 adult controls without the disease). Genomic DNA was extracted from blood leukocytes, and genotyping was performed using PCR followed by direct sequencing. GSTM1 and GSTT1 deletion variants were screened by agarose gel analysis. Individual SNP analysis showed that no specific variants conferred an elevated risk for developing POAG. However, the CG genotype for rs5335 polymorphism in EDNRA showed a protective effect against the development of POAG, as it provides an estimated odds ratio of 0.5 (95% CI, 0.3-0.9; p = 0.03). Moreover, one haplotype consisting of rs1056827 and rs100012 in CYP1B1 gene was significantly associated with a protective effect against POAG (p = 0.0045; OR = 0.3; 95% CI, 0.1-0.7). This is the first case-control investigation of POAG-risk alleles in multiple genes in a Latino population. Although our results support that the analyzed variants are not major risk factors for POAG in this ethnic group, they also point toward a protective effect conferred by EDNRA rs5335, as well as by a CYP1B1 haplotype consisting of rs1056827 and rs100012. Our study emphasizes the importance of genotyping ethnic groups with a complex admixture of ancestral populations for contributing to dissecting the genetics of POAG.