Inherited retinal diseases (IRDs) encompass a variety of disease phenotypes and are known to display both clinical and genetic heterogeneity. A further complexity is that for several IRD-associated genes, pathogenic variants have been reported to cause either autosomal dominant (AD) or autosomal recessive (AR) diseases. The possibility of dual inheritance can create a challenge for variant interpretation as well as the genetic counselling of patients. This review aims to determine whether the molecular mechanisms behind the dual inheritance of each IRD-associated gene is well established, not yet properly understood, or if the association is questionable. Each gene is discussed individually in detail due to different protein structures and functions, but there are overlapping characteristics. For example, eight genes only have a limited number of reported pathogenic variants or a hotspot region implicated in the second inheritance pattern. Whereas CRX and RP1 display distinct spatial patterns for AR and AD pathogenic variants based on the variant type and/or location. The genes with a questionable dual inheritance, namely AIPL1, CRB1, and RCBTB1 highlight the importance of carefully considering allele frequency data. Finally, the crucial role relevant functional studies in animal and cell models play in validating a variant's biochemical or molecular effect is emphasised.

中文翻译：

---

双遗传模式：具有不同分子机制的一系列非综合征遗传性视网膜疾病表型


遗传性视网膜疾病 （IRD） 包括多种疾病表型，并且已知表现出临床和遗传异质性。进一步的复杂性是，对于几个 IRD 相关基因，据报道，致病性变异会导致常染色体显性遗传 （AD） 或常染色体隐性遗传 （AR） 疾病。双重遗传的可能性可能给变异解释以及患者的遗传咨询带来挑战。本综述旨在确定每个 IRD 相关基因双重遗传背后的分子机制是否已明确，尚未得到充分理解，或者这种关联是否值得怀疑。由于蛋白质结构和功能不同，每个基因都单独详细讨论，但存在重叠的特征。例如，八个基因只有有限数量的已报道致病性变异或与第二种遗传模式有关的热点区域。而 CRX 和 RP1 根据变异类型和/或位置显示 AR 和 AD 致病性变异的不同空间模式。具有可疑双遗传的基因，即 AIPL1、CRB1 和 RCBTB1，凸显了仔细考虑等位基因频率数据的重要性。最后，强调了动物和细胞模型中的相关功能研究在验证变异的生化或分子效应方面发挥的关键作用。