Medical Genetics and Ophthalmic Genomics Unit, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Otorhinolaryngology-Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Genes (Basel). 2022 Feb 24;13(3):411. doi: 10.3390/genes13030411.
Anterior segment dysgenesis (ASD) encompasses a wide spectrum of developmental abnormalities of the anterior ocular segment, including congenital cataract, iris hypoplasia, aniridia, iridocorneal synechiae, as well as Peters, Axenfeld, and Rieger anomalies. Here, we report a large five-generation Caucasian family exhibiting atypical syndromic ASD segregating with a novel truncating variant of . The family history is consistent with highly variable autosomal dominant symptoms including isolated glaucoma, iris hypoplasia, aniridia, cataract, hypothyroidism, and congenital heart anomalies. Whole-exome sequencing revealed a novel variant [c.313_314insA; p.(Tyr105*)] in that disrupts the α-helical region of the DNA-binding forkhead box domain. In vitro studies using a heterologous cell system revealed aberrant cytoplasmic localization of FOXC1 harboring the Tyr105* variant, likely precluding downstream transcription function. Meta-analysis of the literature highlighted the intrafamilial variability related to FOXC1 truncating alleles. This study highlights the clinical variability in ASD and signifies the importance of combining both clinical and molecular analysis approaches to establish a complete diagnosis.
前段发育不良（ASD）包括前段眼部的广泛发育异常，包括先天性白内障、虹膜发育不全、无虹膜、虹膜角膜黏连以及 Peters、Axenfeld 和 Rieger 异常。在这里，我们报告了一个大型的五代白种人家系，表现出与新型截断变异体 相关的非典型综合征性 ASD。家族史与高度可变的常染色体显性症状一致，包括孤立性青光眼、虹膜发育不全、无虹膜、白内障、甲状腺功能减退和先天性心脏异常。全外显子组测序显示，FOXC1 中存在一个新型变异 [c.313_314insA;p.(Tyr105*)]，该变异破坏了 DNA 结合叉头框结构域的α螺旋区。使用异源细胞系统进行的体外研究显示，携带 Tyr105*变异的 FOXC1 发生异常的细胞质定位，可能阻止了下游的转录功能。文献的荟萃分析强调了与 FOXC1 截断等位基因相关的家族内变异性。本研究强调了 ASD 的临床变异性，并表明了将临床和分子分析方法相结合以建立完整诊断的重要性。
