Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study.
Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study.
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DOI：
10.1016/j.ophtha.2022.02.010
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发表时间：
2022-06
期刊：
影响因子：
13.7
通讯作者：
Thomas, Mervyn G.
中科院分区：
文献类型：
--
作者：
Kuht, Helen J.;Maconachie, Gail D. E.;Han, Jinu;Kessel, Line;van Genderen, Maria M.;McLean, Rebecca J.;Hisaund, Michael;Tu, Zhanhan;Hertle, Richard W.;Gronskov, Karen;Bai, Dayong;Wei, Aihua;Li, Wei;Jiao, Yonghong;Smirnov, Vasily;Choi, Jae-Hwan;Tobin, Martin D.;Sheth, Viral;Purohit, Ravi;Dawar, Basu;Girach, Ayesha;Strul, Sasha;May, Laura;Chen, Fred K.;Jeffery, Rachael C. Heath;Aamir, Abdullah;Sano, Ronaldo;Jin, Jing;Brooks, Brian P.;Kohl, Susanne;Arveiler, Benoit;Montoliu, Lluis;Engle, Elizabeth C.;Proudlock, Frank A.;Nishad, Garima;Pani, Prateek;Varma, Girish;Gottlob, Irene;Thomas, Mervyn G.
关键词：
为了确定中央凹发育不全（FH）的基因型和表型谱，多中心、观察性研究了来自9个国家的12个中心（n=523）或从既往报告文献的公开可用数据集（n=384）中提取的907例确诊白化病、PAX 6、SLC 38 A8、FRMD 7、AHR或色盲（ACHM）分子诊断的患者。在2011年1月至2021年3月期间，从12个中心或文献中确定了经确认的分子诊断和中心凹光学相干断层扫描（OCT）扫描可用性的个体。通过序列分析证实了基因诊断。FH的分级来自OCT。FH分级、是否存在感光细胞特化（PRS+ vs PRS-）、分子诊断和视力（VA）。在我们的队列中，典型FH最常见的遗传病因是白化病（67.5%），其次是PAX 6（21.8%），SLC 38 A8（6.8%）和FRMD 7（3.5%）变体。AHR变异罕见（0.4%）。67.4%的ACHM患者存在不典型FH。与典型FH相比，ACHM中的非典型FH的VA显著更差（p<0.0001）。基于分子诊断的FH分级谱存在显著差异（X2=60.4，p<0.0001）。所有SLC 38 A8病例均为PRS-（p=0.003），而所有FRMD 7病例均为PRS+（p<0.0001）。白化病亚型的分析显示，与眼白化病（OA）和Hermansky-Pudlak综合征（HPS）相比，眼皮肤白化病（OCA）之间的FH（X2=31.4，p<0.0001）和VA（p=0.0003）分级存在显著差异。OA和HPS的FH分级高于OCA，VA较差。与FH相关的其他诊断相比，FRMD 7变体之间的VA存在显著差异（p<0.0001）。我们表征了FH的表型和基因型谱。与所有其他形式的FH相比，非典型FH与更差的预后相关。在典型的FH中，我们的数据表明，视网膜发育停滞在SLC 38 A8、OA、HPS和AHR变体中发生得更早，而在FRMD 7变体中发生得更晚。OCA和PAX 6变体的中央凹发育停滞的限定时间段似乎表现出更多的变异性。我们的研究结果提供了与FH相关的疾病机制的见解，也有显着的预后和诊断价值。我们观察了基于基因型的中心凹发育停滞的独特模式，并强调了与诊断和预后直接临床相关的机制意义。这有助于优先考虑基因检测、后续咨询和支持。
To characterise the genotypic and phenotypic spectrum of foveal hypoplasia (FH) Multi-centre, observational study 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR or achromatopsia (ACHM) from twelve centres in nine countries (n=523), or, extracted from publicly available datasets from previously reported literature (n=384). Individuals with a confirmed molecular diagnosis and availability of foveal optical coherence tomography (OCT) scans were identified from twelve centres or from the literature, between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCTs. Grade of FH, presence or absence of photoreceptor specialisation (PRS+ vs PRS−), molecular diagnosis and visual acuity (VA). The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%) and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of ACHM cases. Atypical FH in ACHM had significantly worse VA compared to typical FH (p<0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (X2=60.4, p<0.0001). All SLC38A8 cases were PRS− (p=0.003), while all FRMD7 cases were PRS+ (p<0.0001). Analysis of albinism sub-types revealed a significant difference in the grade of FH (X2=31.4, p<0.0001) and VA (p=0.0003) between oculocutaneous albinism (OCA) compared to ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). OA and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (p<0.0001) in VA between FRMD7 variants compared to other diagnoses associated with FH. We characterised the phenotypic and genotypic spectrum of FH. Atypical FH is associated with much worse prognosis compared to all other forms of FH. In typical FH, our data suggests that arrested retinal development occurs earlier in SLC38A8, OA, HPS and AHR variants and much later in FRMD7 variants. The defined time-period of foveal developmental arrest for OCA and PAX6 variants appears to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and also have significant prognostic and diagnostic value. We observe distinctive patterns of arrested foveal development based on genotype and highlight the mechanistic implications with direct clinical relevance to diagnosis and prognosis. This helps prioritise genetic testing, subsequent counselling, and support.
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