Dataset Information

Association of Clinical and Genetic Heterogeneity With BEST1 Sequence Variations.

ABSTRACT:

Importance

Detailed phenotypic information on the spectrum of fundus abnormalities and clinical variability of all phenotypes associated with sequence variations in BEST1 is limited.

Objective

To report a detailed phenotypic and genetic analysis of a patient cohort with sequence variations in BEST1.

Design, setting, and participants

This retrospective case series took place at the Oxford Eye Hospital in Oxford, UK. Thirty-six patients from a single center with disease-causing sequence variations in BEST1 from 25 different families were analyzed. Data were collected from November 2017 to June 2018, and analysis began April 2018.

Main outcomes and measures

Results of ocular phenotyping and genetic testing using targeted next-generation sequencing to identify BEST1 sequence variations.

Results

Thirty-six patients from 25 families with disease-causing sequence variations in BEST1 were included. Of 36 patients, 20 (55.6%) were female. Three distinct clinical phenotypes were identified: autosomal recessive bestrophinopathy (ARB), best vitelliform macular dystrophy (BVMD), and adult-onset vitelliform macular dystrophy. The ARB phenotype group comprised 18 patients from 9 families with age in years at symptom onset ranging from less than 10 to 40s. All patients showed a common phenotype of fundus autofluorescence abnormalities, and spectral-domain optical coherence tomography features were similar in all patients with schitic and cystoid changes. A phenotype of a beaten metallic retinal appearance extending from the mid periphery to the far periphery was identified in 8 patients. Four patients from 1 family with ARB were previously reported to have autosomal recessive retinitis pigmentosa but were reclassified as having ARB as part of this study. The BVMD phenotype group comprised 16 patients from 14 families with age at symptom onset ranging from less than 10 to 70s. Fundus features were localized to the macula and consistent with the stage of BVMD. In the adult-onset vitelliform macular dystrophy phenotype group, the age in years at symptom onset varied from 50s to 70s in 2 patients from 2 families. Fundus features included small vitelliform lesions. Where available, electro-oculogram results demonstrated a reduced or absent light rise in all patients with ARB and BVMD. Genetic testing identified 22 variants in BEST1.

Conclusions and relevance

These findings support the notion that ARB, BVMD, and adult-onset vitelliform macular dystrophy are clinically distinct and recognizable phenotypes and suggest that the association of autosomal recessive retinitis pigmentosa with sequence variations in BEST1 should be rereviewed.

SUBMITTER: Shah M

PROVIDER: S-EPMC7118667 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeMutations in bestrophin 1 (BEST1) are associated with a group of retinal disorders known as bestrophinopathies in man and canine multifocal retinopathies (cmr) in the dog. To date, the dog is the only large animal model suitable for the complex characterization and in-depth studies of Best-related disorders. In the first report of cmr, the disease was described in a group of mastiff-related breeds (cmr1) and the Coton de Tulear (cmr2). Additional breeds, e.g., the Lapponian herder (LH) and others, subsequently were recognized with similar phenotypes, but linked loci are unknown. Analysis of the BEST1 gene aimed to identify mutations in these additional populations and extend our understanding of genotype-phenotype associations.MethodsAnimals were subjected to routine eye exams, phenotypically characterized, and samples were collected for molecular studies. Known BEST1 mutations were assessed, and the canine BEST1 coding exons were amplified and sequenced in selected individuals that exhibited a cmr compatible phenotype but that did not carry known mutations. Resulting sequence changes were genotyped in several different breeds and evaluated in the context of the phenotype.ResultsSeven novel coding variants were identified in exon 10 of cBEST1. Two linked mutations were associated with cmr exclusive to the LH breed (cmr3). Two individuals of Jämthund and Norfolk terrier breeds were heterozygous for two conservative changes, but these were unlikely to have disease-causing potential. Another three substitutions were found in the Bernese mountain dog that were predicted to have a deleterious effect on protein function. Previously reported mutations were excluded from segregation in these populations, but cmr1 was confirmed in another mastiff-related breed, the Italian cane corso.ConclusionsA third independent canine model for human bestrophinopathies has been established in the LH breed. While exhibiting a phenotype comparable to cmr1 and cmr2, the novel cmr3 mutation is predicted to be based on a distinctly different molecular mechanism. So far cmr2 and cmr3 are exclusive to a single dog breed each. In contrast, cmr1 is found in multiple related breeds. Additional sequence alterations identified in exon 10 of cBEST1 in other breeds exhibit potential disease-causing features. The inherent genetic and phenotypic variation observed with retinal disorders in canines is complicated further by cmr3 being one of four distinct genetic retinal traits found to segregate in LH. Thus, a combination of phenotypic, molecular, and population analysis is required to establish a strong phenotype-genotype association. These results indicate that cmr has a larger impact on the general dog population than was initially suspected. The complexity of these models further confirms the similarity to human bestrophinopathies. Moreover, analyses of multiple canine models will provide additional insight into the molecular basis underlying diseases caused by mutations in BEST1.