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

Abstract

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.

Human brain organoids assemble functionally integrated bilateral optic vesicles

“…Further investigation of marker genes revealed the presence of two more clusters of developing optic vesicle (C6) and a pre-optic region (C7) expressing early transcription factors TFAP2A/B and LIM homeobox gene LHX1 essential for optic fissure closure and precise timing of neural retina differentiation ( Figure 2A-B). TFAP2A expression has also been detected in the lens and neural retina and mutations in TFAP2A is associated with branchio-oculo-facial syndrome (BOFS) in which its associated structures are defective (Min et al, 2020). On the other hand, LHX1 is expressed in the forebrain at a time point that parallels to the formation of neural retina (Inoue et al, 2013).…”

A bird’s eye view on the use of whole exome sequencing in rare congenital ophthalmic diseases

“…A TFAP2A missense variant was identified in a patient affected by chorioretinal and optic nerve coloboma (A153). TFAP2A monoallelic variants are associated to the branchio-oculo-facial syndrome (BOFS; OMIM #113620), characterized by branchial cleft sinus defects, ocular anomalies, and cleft or pseudocleft lip/palate [ 27 ]. BOFS is a distinctive and rare condition; the presence of phenotypic heterogeneity associated with specific genetic variants is still to be investigated.…”