Wolfram Lasse, Merle David A, Kühlewein Laura, Reith Milda, Kempf Melanie, Stingl Krunoslav, Haack Tobias, Mazzola Pascale, Poths Karin, Weisschuh Nicole, Wissinger Bernd, Kohl Susanne, Stingl Katarina
Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany.
Department for Ophthalmology, Institute for Ophthalmic Research, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany.
BMC Ophthalmol. 2025 Apr 23;25(1):239. doi: 10.1186/s12886-025-04048-1.
This study investigates the clinical manifestations of inherited retinal diseases (IRD) associated with dual-gene variant constellations involving biallelic ABCA4 variants.
We assess four cases for their unique phenotypic outcomes due to biallelic ABCA4 variants and additional genotypes in CACNA1F, IMPG1, HK1 and MYO7A, respectively.
This study investigates the phenotypic impact of dual-gene variants, including biallelic ABCA4 variants and additional retinal gene variants in CACNA1F, IMPG1, HK1 and MYO7A. In MST465-II:1, the ABCA4-CACNA1F constellation led to progressive macular atrophy and night blindness, with nystagmus linked to CACNA1F. In MST448-II:1, ABCA4 variants primarily contributed to a macular dystrophy, while the IMPG1 variant had no obvious impact, suggesting it may be a benign polymorphism. In SRP1400-II:1, a de novo HK1 variant caused retinitis pigmentosa (RP)-like retinal degeneration and intellectual disability and in USHI105-II:1, MYO7A variants primarily resulted in an Usher syndrome 1 phenotype. In both latter cases, ABCA4 variants play a more subtle role. These findings illustrate the importance of critical phenotype and genotype assessment and how complex interactions between ABCA4 and other genetic variants can configure the phenotype, making it challenging to distinguish the contributions of each gene.
This study underscores the importance of advanced diagnostic tools and careful genotype evaluation to accurately identify and understand potential complex genetic interactions in IRDs. The observed phenotypes enhance our understanding of how these genes contribute to human retinal function and dysfunction. Furthermore, these insights can impact clinical decision-making, as patients with dual-gene variant constellations might experience questionable benefit from potential future gene therapies. Thus, careful patient selection and complete genotype and phenotype assessment before treatment is essential to manage potential risks and costs effectively.
本研究调查与涉及双等位基因ABCA4变异的双基因变异组合相关的遗传性视网膜疾病（IRD）的临床表现。
我们分别评估了4例因双等位基因ABCA4变异以及CACNA1F、IMPG1、HK1和MYO7A中的其他基因型而产生的独特表型结果。
本研究调查了双基因变异的表型影响，包括双等位基因ABCA4变异以及CACNA1F、IMPG1、HK1和MYO7A中的其他视网膜基因变异。在MST465-II:1中，ABCA4-CACNA1F组合导致进行性黄斑萎缩和夜盲，眼球震颤与CACNA1F有关。在MST448-II:1中，ABCA4变异主要导致黄斑营养不良，而IMPG1变异没有明显影响，表明它可能是一种良性多态性。在SRP1400-II:1中，一个新发的HK1变异导致色素性视网膜炎（RP）样视网膜变性和智力残疾，在USH105-II:1中，MYO7A变异主要导致1型Usher综合征表型。在后两种情况下，ABCA4变异起的作用更为微妙。这些发现说明了关键表型和基因型评估的重要性，以及ABCA4与其他基因变异之间复杂的相互作用如何塑造表型，使得区分每个基因的作用具有挑战性。
本研究强调了先进诊断工具和仔细的基因型评估对于准确识别和理解IRD中潜在复杂基因相互作用的重要性。观察到的表型增强了我们对这些基因如何影响人类视网膜功能和功能障碍的理解。此外，这些见解可能会影响临床决策，因为具有双基因变异组合的患者可能无法从未来潜在的基因治疗中明显获益。因此，在治疗前仔细选择患者并进行完整的基因型和表型评估对于有效管理潜在风险和成本至关重要。
