Importance Keratoglobus is a rare corneal disorder characterized by generalized thinning and globular protrusion of the cornea. Affected individuals typically have significantly decreased vision and are at risk of corneal perforation. The genetic basis and inheritance pattern of isolated congenital keratoglobus are currently unknown.

Objective To identify the genetic basis of isolated congenital keratoglobus.

Design, Setting, and Participants This case series and molecular analysis studied 3 unrelated nonconsanguineous families with keratoglobus at a medical center in Israel. Data were collected from June 2019 to March 2021 and analyzed during the same period.

Exposures Whole-exome sequencing and direct Sanger sequencing, expression analysis by real-time polymerase chain reaction, splice-site variant analysis, immunohistochemical staining, and histological evaluation of a knockout mouse model.

Main Outcomes and Measure Molecular characteristics associated with keratoglobus.

Results Four pediatric patients (3 male individuals) from 3 families had clinical findings consistent with keratoglobus. These included globular protrusion, corneal thinning more prominent at the periphery, and high astigmatism. Truncating and splice site variants were identified in the TMEM45A gene, which fully segregate with the disorder. All affected individuals were homozygous or compound heterozygous for variants in the TMEM45A gene, while unaffected family members were heterozygous carriers. Expression analysis in healthy controls showed that TMEM45A was expressed 23 times higher in the human cornea compared with peripheral blood. Immunohistochemical staining of the TMEM45A protein in normal corneas confirmed its expression in the corneal stroma and epithelium. A TMEM45A knockout mouse model showed structural features consistent with keratoglobus.

Conclusions and Relevance Expression of TMEM45A has been previously shown to result in upregulation of extracellular matrix components and fibrosis. These results suggest that isolated congenital keratoglobus is an autosomal recessively inherited disorder associated with variants in the TMEM45A gene.

重要性 角膜球菌是一种罕见的角膜疾病，其特征是角膜普遍变薄和球状突出。受影响的个体通常视力显着下降并且有角膜穿孔的风险。孤立的先天性角膜球菌的遗传基础和遗传模式目前尚不清楚。

目的 确定孤立性先天性角膜球菌的遗传基础。

设计、设置和参与者 该病例系列和分子分析研究了以色列一家医疗中心的 3 个不相关的非血缘角膜球菌家庭。数据收集时间为 2019 年 6 月至 2021 年 3 月，并在同一时期进行了分析。

曝光 全外显子组测序和直接 Sanger 测序、实时聚合酶链反应表达分析、剪接位点变异分析、免疫组织化学染色和敲除小鼠模型的组织学评估。

主要结果和测量 与角膜球相关的分子特征。

结果 来自 3 个家庭的 4 名儿科患者（3 名男性个体）的临床表现与角膜球一致。这些包括球状突出、周边更明显的角膜变薄和高度散光。在TMEM45A基因中鉴定出截断和剪接位点变体，它们与疾病完全分离。对于TMEM45A基因中的变体，所有受影响的个体都是纯合子或复合杂合子，而未受影响的家庭成员是杂合子携带者。健康对照中的表达分析表明TMEM45A与外周血相比，在人角膜中的表达量高出 23 倍。正常角膜中 TMEM45A 蛋白的免疫组织化学染色证实了其在角膜基质和上皮中的表达。TMEM45A敲除小鼠模型显示出与角膜球一致的结构特征。

结论和相关性 TMEM45A的表达先前已被证明会导致细胞外基质成分和纤维化的上调。这些结果表明，孤立的先天性角膜球是一种常染色体隐性遗传疾病，与TMEM45A基因的变异有关。