BMC Ophthalmology (Apr 2025)

Clinical manifestations of dual-gene variants involving ABCA4 in retinal dystrophies

  • Lasse Wolfram,
  • David A. Merle,
  • Laura Kühlewein,
  • Milda Reith,
  • Melanie Kempf,
  • Krunoslav Stingl,
  • Tobias Haack,
  • Pascale Mazzola,
  • Karin Poths,
  • Nicole Weisschuh,
  • Bernd Wissinger,
  • Susanne Kohl,
  • Katarina Stingl

DOI
https://doi.org/10.1186/s12886-025-04048-1
Journal volume & issue
Vol. 25, no. 1
pp. 1 – 13

Abstract

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Abstract Background This study investigates the clinical manifestations of inherited retinal diseases (IRD) associated with dual-gene variant constellations involving biallelic ABCA4 variants. Methods We assess four cases for their unique phenotypic outcomes due to biallelic ABCA4 variants and additional genotypes in CACNA1F, IMPG1, HK1 and MYO7A, respectively. Results 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. Conclusions 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.

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