目的:描述与p.Pro101ThrBEST1变体相关的视网膜表型。
方法:回顾性,观察案例系列。
方法:被诊断为有蛇床子病的患者,其中分子遗传学检测确定了p.Pro101ThrBEST1,以及其一级亲属中的健康携带者。
方法:查阅病历以获取家族史和眼科检查数据,包括视网膜成像.成像协议包括光学相干断层扫描(OCT),和使用SpectralisHRA+OCT的眼底自发荧光(海德堡工程,海德堡,德国)。通过下一代测序进行遗传分析。
方法:眼科检查结果,视网膜表型的多模态影像学特征。
结果:c.301C>A,p.Pro101ThrBEST1错义变体被确定为来自5个家庭的8个个体(所有男性)的致病变体,占13%的病例(8/61)和10%的致病等位基因(9/93),在我们的队列中,受bestrophinophis影响的患者。7个人(14只眼)具有杂合状态的变异:所有眼睛都有远视性屈光不正(中值球面当量为3.75D),4人患有黄斑营养不良,视力轻度下降(中位数为20/25Snellen),而其他三人是无症状携带者。关于多模式视网膜成像,14只眼睛中有5只(36%)患有亚临床性视黄酶病,4例(29%)有典型的成人发作的中央孔卵黄样营养不良,其余5例(36%)表现出营养不良样表型。有6名受试者的随访数据,证明了长达11年的临床稳定性,亚临床和临床形式。发现另一位常染色体隐性遗传的bestrophinopathy患者具有纯合性p.Pro101Thr变体。
结论:p.Pro101ThrBEST1变种可能是意大利人群中发生色氨酸病的常见原因,并可导致常染色体显性遗传性黄斑营养不良,外显率不完全和轻度临床表现,以及常染色体隐性遗传的Betrophinopathy。常染色体显性遗传性黄斑病变的范围包括典型的成人发作的中央眼窝卵黄样营养不良和模式营养不良样表型。
OBJECTIVE: To describe the retinal phenotype associated with the p.Pro101Thr BEST1 variant.
METHODS: Retrospective, observational case series.
METHODS: Patients diagnosed with bestrophinopathies in which molecular genetic testing identified the p.Pro101Thr BEST1 as well as healthy carriers among their first-degree relatives.
METHODS: Medical records were reviewed to obtain data on family history and ophthalmic examinations, including retinal imaging. The imaging protocol included OCT and fundus autofluorescence using Spectralis HRA + OCT (Heidelberg Engineering). Genetic analysis was performed by next-generation sequencing.
METHODS: Results of ophthalmic examinations and multimodal imaging features of retinal phenotypes.
RESULTS: The c.301C>A, p.Pro101Thr BEST1 missense variant was identified as the causative variant in 8 individuals (all men) from 5 families, accounting for 13% of cases (8/61) and 10% of pathogenic alleles (9/93) in our cohort of patients affected by bestrophinopathies. Seven individuals (14 eyes) had the variant in heterozygous status: all eyes had a hyperopic refractive error (median spherical equivalent of + 3.75 diopters [D]) and 4 individuals had a macular dystrophy with mildly reduced visual acuity (median of 20/25 Snellen), whereas the other 3 were asymptomatic carriers. On multimodal retinal imaging, 5 (36%) out of 14 eyes had subclinical bestrophinopathy, 4 (29%) had typical findings of adult-onset foveomacular vitelliform dystrophy (AOFVD), and the remaining 5 (36%) displayed a pattern dystrophy-like phenotype. Follow-up data were available for 6 subjects, demonstrating clinical stability up to 11 years, in both subclinical and clinical forms. An additional patient with autosomal recessive bestrophinopathy was found to harbor the p.Pro101Thr variant in homozygosity.
CONCLUSIONS: The p.Pro101Thr BEST1 variant is likely a frequent cause of bestrophinopathy in the Italian population and can result in autosomal dominant macular dystrophies with incomplete penetrance and mild clinical manifestations as well as autosomal recessive bestrophinopathy. The spectrum of autosomal dominant maculopathy includes the typical AOFVD and a pattern dystrophy-like phenotype.
BACKGROUND: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.