Complex microphthalmia is characterized by small eyes with additional abnormalities that may include anterior segment dysgenesis. While many genes are known, a genetic cause is identified in only 4–30% of microphthalmia, with the lowest rate in unilateral cases. We identified four novel pathogenic loss‐of‐function alleles in PRR12 in families affected by complex microphthalmia and/or Peters anomaly, including two de novo, the first dominantly transmitted allele, as well as the first splicing variant. The ocular phenotypes were isolated with no additional systemic features observed in two unrelated families. Remarkably, ocular phenotypes were asymmetric in all individuals and unilateral (with structurally normal contralateral eye) in three. There are only three previously reported PRR12 variants identified in probands with intellectual disability, neuropsychiatric disorders, and iris anomalies. While some overlap with previously reported cases is seen, nonsyndromic developmental ocular anomalies are a novel phenotype for this gene. Additional phenotypic expansions included short stature and normal development/cognition, each noted in two individuals in this cohort, as well as absence of neuropsychiatric disorders in all. This study identifies new associations for PRR12 disruption in humans and presents a genetic diagnosis resulting in unilateral ocular phenotypes in a significant proportion of cases.

中文翻译：

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PRR12 的主要变异导致单侧或双侧复杂性小眼炎

复杂性小眼症的特征是小眼睛伴有额外的异常，可能包括眼前节发育不全。虽然许多基因是已知的，但仅在 4-30% 的小眼病中发现了遗传原因，单侧病例的发病率最低。我们在受复杂性小眼病和/或 Peters 异常影响的家庭中鉴定了PRR12中四个新的致病性功能丧失等位基因，包括两个从头，第一个显性传播的等位基因，以及第一个剪接变体。眼表型是孤立的，在两个不相关的家族中没有观察到额外的全身特征。值得注意的是，所有个体的眼表型都是不对称的，三个是单侧的（对侧眼结构正常）。先前报道的 PRR12只有三个在智力残疾、神经精神疾病和虹膜异常的先证者中发现的变异。虽然可以看到与先前报道的病例有一些重叠，但非综合征发育性眼部异常是该基因的一种新表型。额外的表型扩展包括身材矮小和正常发育/认知，在该队列中的两个个体中都注意到，并且完全没有神经精神疾病。这项研究确定了人类PRR12破坏的新关联，并提出了一种基因诊断，导致大部分病例出现单侧眼表型。