PAX6 is considered the master regulator of eye development, the majority of variants affecting this gene cause the pan-ocular developmental eye disorder aniridia. Although no genotype-phenotype correlations are clearly established, missense variants affecting the DNA-binding paired domain of PAX6 are usually associated with non-aniridia phenotypes like microphthalmia, coloboma or isolated foveal hypoplasia. In this study, we report two missense heterozygous variants in the paired domain of PAX6 resulting in isolated foveal hypoplasia with nystagmus in two independent families: c.112 C > G; p.(Arg38Gly) and c.214 G > C; p.(Gly72Arg) in exons 5 and 6, respectively. Furthermore, we provide evidence that paternal postzygotic mosaicism is the cause of inheritance, with clinically unaffected fathers and reduced affected allele fraction. This work contributes to increase the phenotypic spectrum caused by PAX6 variants, and to our knowledge, is the first report to describe the presence of postzygotic parental mosaicism causing isolated foveal hypoplasia with nystagmus. These results support the growing evidence that suggest an overestimation of sporadic cases with PAX6 variants, which has strong implications for both genetic counselling and family planning.

PAX6 被认为是眼睛发育的主要调节因子，影响该基因的大多数变异导致全眼发育性眼部疾病无虹膜。尽管没有明确建立基因型-表型相关性，但影响 PAX6 的 DNA 结合配对结构域的错义变异通常与非无虹膜表型相关，如小眼症、缺损或孤立的中央凹发育不全。在这项研究中，我们报告了 PAX6 配对结构域中的两个错义杂合变体，导致两个独立家族中孤立的中心凹发育不全伴眼球震颤：c.112 C > G；p.(Arg38Gly) 和 c.214 G > C；p.(Gly72Arg) 分别在外显子 5 和 6 中。此外，我们提供的证据表明，父亲合子后嵌合体是遗传的原因，临床上未受影响的父亲和受影响的等位基因分数减少。据我们所知，PAX6变体是第一份描述存在导致孤立性中心凹发育不全伴眼球震颤的合子后父母嵌合体的报告。这些结果支持越来越多的证据表明高估了PAX6变异的散发病例，这对遗传咨询和计划生育都有重要影响。