Table_4_A Heterozygous Novel Mutation in TFAP2A Gene Causes Atypical Branchio-Oculo-Facial Syndrome With Isolated Coloboma of Choroid: A Case Report.DOCX

Background: Branchio-oculo-facial syndrome (BOFS) is a rare congenital developmental disorder with highly variable clinical phenotypes in autosomal dominant inheritance. The aim of this study is to identify disease-causing mutations in a Chinese family with predominant coloboma of choroid.
Case report: We described a family (a mother and her daughter) with unclear clinical diagnosis. The mother (proband) presented with bilateral coloboma of choroid, whereas her daughter had a relatively severe phenotype and presented with larger bilateral choroid coloboma and high-vaulted arch. We applied the next generation sequencing (NGS) panel and analyzed 776 genes related to inherited ocular disorders on the proband. Four candidate heterozygous variants in four genes, respectively, were detected in the proband. Validation of these variants were subsequently performed in the family using Sanger sequencing. Among these variants, a novel nonsense mutation c.912C>A, p.(Cys304*) (NM_001042425.2) which in exon 6 of the conserved helix-span-helix domain in TFAP2A results in a premature termination codon. It may trigger nonsense-mediated mRNA decay (NMD). Both the affected mother and daughter had this variant, whereas it was absent in the asymptomatic father. Together with the silicon tools and clinical features, we concluded that the variant c.912C>A, p.(Cys304*), was the second reported nonsense mutation in TFAP2A gene, which was the disease-causing mutation of the family.
Conclusion: There are many hereditary diseases accompanied by ocular anomalies. For instance, BOFS, patients with atypical features are always at risk of being under-diagnosed. NGS is a powerful method to identify the genetic cause and improve genetic counseling for less clarified hereditary ocular diseases.

背景：鳃-眼-面综合征（Branchio-oculo-facial syndrome, BOFS）是一种罕见的常染色体显性遗传性先天性发育障碍，临床表型具有高度异质性。本研究旨在明确一个以脉络膜缺损为主要临床表现的中国家系的致病突变。

病例报告：本研究报道了一个临床诊断不明的家系（母亲与其女儿）。先证者为母亲，表现为双侧脉络膜缺损；其女儿表型相对更严重，可见双侧大范围脉络膜缺损伴高拱腭。我们对先证者应用下一代测序（next generation sequencing, NGS）靶向基因测序panel，分析了776个与遗传性眼病相关的基因。在先证者中检测到4个基因各携带1个候选杂合变异。随后采用Sanger测序对该家系成员进行变异验证。其中，TFAP2A基因第6外显子存在1个新型无义突变c.912C>A，p.(Cys304*)（NM_001042425.2），该突变位于该基因保守的螺旋-跨膜-螺旋结构域内，可产生提前终止密码子，可能触发无义介导的mRNA降解（nonsense-mediated mRNA decay, NMD）。受累的母亲与女儿均携带该变异，而无症状的父亲未携带该变异。结合生物信息学工具分析结果与临床表型，我们判定该c.912C>A，p.(Cys304*)变异是TFAP2A基因上第二例被报道的无义突变，为本家系的致病突变。

结论：诸多遗传性疾病均可伴随眼部异常，以鳃-眼-面综合征（BOFS）为例，存在非典型表型的患者常易被漏诊。下一代测序（NGS）是明确遗传性眼病遗传病因、优化遗传咨询的有效手段。