PURPOSE To investigate intersibling phenotypic concordance in Stargardt disease (STGD1). DESIGN Retrospective cohort study. PARTICIPANTS Siblings with genetically confirmed STGD1 and at least 1 available fundus autofluorescence (FAF) image of both eyes. METHODS We compared age at onset within families. Disease duration was matched to investigate differences in best-corrected visual acuity (BCVA) and compared the survival time for reaching severe visual impairment (<20/200 Snellen or >1.0 logarithm of the minimum angle of resolution [logMAR]). Central retinal atrophy area was quantified independently by 2 experienced graders using semiautomated software and compared between siblings. Both graders performed qualitative assessment of FAF and spectral-domain (SD) OCT images to identify phenotypic differences. MAIN OUTCOME MEASURES Differences in age at onset, disease duration-matched BCVA, time to severe visual impairment development, FAF atrophy area, FAF patterns, and genotypes. RESULTS Substantial differences in age at onset were present in 5 of 17 families, ranging from 13 to 39 years. Median BCVA at baseline was 0.60 logMAR (range, -0.20 to 2.30 logMAR; Snellen equivalent, 20/80 [range, 20/12-hand movements]) in the right eye and 0.50 logMAR (range, -0.20 to 2.30 logMAR; Snellen equivalent, 20/63 [range, 20/12-hand movements]) in the left eye. Disease duration-matched BCVA was investigated in 12 of 17 families, and the median difference was 0.41 logMAR (range, 0.00-1.10 logMAR) for the right eye and 0.41 logMAR (range, 0.00-1.08 logMAR) for the left eye. We observed notable differences in time to severe visual impairment development in 7 families, ranging from 1 to 29 years. Median central retinal atrophy area was 11.38 mm2 in the right eye (range, 1.98-44.78 mm2) and 10.59 mm2 in the left eye (range, 1.61-40.59 mm2) and highly comparable between siblings. Similarly, qualitative FAF and SD OCT phenotypes were highly comparable between siblings. CONCLUSIONS Phenotypic discordance between siblings with STGD1 carrying the same ABCA4 variants is a prevalent phenomenon. Although the FAF phenotypes are highly comparable between siblings, functional outcomes differ substantially. This complicates both sibling-based prognosis and genotype-phenotype correlations and has important implications for patient care and management.

中文翻译：

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患有Stargardt疾病的兄弟姐妹中高度易变的疾病课程。

目的研究Stargardt病（STGD1）中的表型一致性。设计回顾性队列研究。参与者具有遗传学确认的STGD1的兄弟姐妹，且双眼至少有1个可用的眼底自发荧光（FAF）图像。方法我们比较了家庭中发病的年龄。匹配疾病持续时间以调查最佳矫正视力（BCVA）的差异，并比较达到严重视力障碍（<20/200 Snellen或最小分辨角[logMAR]的> 1.0对数）的生存时间。中央视网膜萎缩面积由2位经验丰富的分级人员使用半自动化软件独立进行量化，并在兄弟姐妹之间进行比较。两名评分员都对FAF和光谱域（SD）OCT图像进行了定性评估，以识别表型差异。主要观察指标发病年龄，疾病持续时间相匹配的BCVA，严重视力障碍发生时间，FAF萎缩面积，FAF模式和基因型的差异。结果17个家庭中有5个的发病年龄存在实质性差异，范围从13岁到39岁。基线时右眼的BCVA中位数为0.60 logMAR（范围-0.20至2.30 logMAR； Snellen当量，20/80 [范围，20/12手动作]），0.50 logMAR（范围-0.20至2.30 logMAR； Snellen）相当于左眼20/63 [范围，20/12手动作]）。在17个家庭中的12个家庭中调查了疾病持续时间匹配的BCVA，右眼的中位数差异为0.41 logMAR（范围为0.00-1.10 logMAR），而左眼的中位数差异为0.41 logMAR（范围为0.00-1.08 logMAR）。我们观察到7个家庭在1到29岁之间发生严重视觉障碍的时间存在显着差异。右眼中位视网膜中央萎缩面积中位数为11.38 mm2（范围1.98-44.78 mm2），左眼中位视网膜中央萎缩面积中位数为10.59 mm2（范围1.61-40.59 mm2），在兄弟姐妹之间具有高度可比性。同样，在兄弟姐妹之间，定性FAF和SD OCT表型具有高度可比性。结论STGD1携带相同ABCA4变体的兄弟姐妹之间的表型不一致是普遍现象。尽管FAF表型在兄弟姐妹之间具有很高的可比性，但功能结局却有很大差异。这使基于同胞的预后和基因型-表型的相关性均变得复杂，并且对患者的护理和管理具有重要意义。右眼为38平方毫米（范围1.98-44.78平方毫米），左眼为10.59平方毫米（范围1.61-40.59平方毫米），兄弟姐妹之间的可比性极高。同样，在兄弟姐妹之间，定性FAF和SD OCT表型具有高度可比性。结论STGD1携带相同ABCA4变体的兄弟姐妹之间的表型不一致是普遍现象。尽管FAF表型在兄弟姐妹之间具有很高的可比性，但功能结局却有很大差异。这使基于同胞的预后和基因型-表型的相关性均变得复杂，并且对患者的护理和管理具有重要意义。右眼为38平方毫米（范围1.98-44.78平方毫米），左眼为10.59平方毫米（范围1.61-40.59平方毫米），兄弟姐妹之间的可比性极高。同样，在兄弟姐妹之间，定性FAF和SD OCT表型具有高度可比性。结论STGD1携带相同ABCA4变体的兄弟姐妹之间的表型不一致是普遍现象。尽管FAF表型在兄弟姐妹之间具有很高的可比性，但功能结局却有很大差异。这使基于同胞的预后和基因型-表型的相关性均变得复杂，并且对患者的护理和管理具有重要意义。结论STGD1携带相同ABCA4变体的兄弟姐妹之间的表型不一致是普遍现象。尽管FAF表型在兄弟姐妹之间具有很高的可比性，但功能结局却有很大差异。这使基于同胞的预后和基因型-表型的相关性均变得复杂，并且对患者的护理和管理具有重要意义。结论STGD1携带相同ABCA4变体的兄弟姐妹之间的表型不一致是普遍现象。尽管FAF表型在兄弟姐妹之间具有很高的可比性，但功能结局却有很大差异。这使基于同胞的预后和基因型-表型的相关性均变得复杂，并且对患者的护理和管理具有重要意义。