Abstract:  Objective To analyze the clinical and genetic characteristics of a family with Axenfeld-Rieger syndrome (ARS). Design Pedigree investigation.  Participants Three subjects from a family with ARS were admitted to Beijing Tongren Hospital. Methods Detailed ophthalmic examination and general examination were performed for family members. Peripheral venous blood was collected and DNA was extracted. Whole exome sequencing (WES) was performed on the proband, and Sanger sequencing and family co-segregation were used to validate disease-causing mutation. Main Outcome Measures Ocular examination results, physical examination results, genotype, craniocerebral MRI. Results Three samples (proband and their parents) were collected in this study. The proband presented bilateral anterior segments dysplasia. Nystagmus, strabismus, glaucoma, fundus manifestations of high myopiaand posterior staphyloma were presented in the proband’s left eye. A general examination suggested mixed deafness in the left ear, mild aortic insufficiency, and cutaneous amyloidosis. Brain MRI showed multiple bilateral leukoencephalopathy. The proband also had craniofacial features such as telecanthus, a high and broad nasal root. The father of the proband had anterior segment manifestations and systemic abnormalities similar to those of the proband. The results of gene testing and bioinformatics analysis indicated that both the proband and his father had an unreported FOXC1 gene insertion mutation NM_001453: c.1043_1044insGGCGCTC, p. (Tyr353fs) (chr6:1611723T> TGGCGCTC, hg19). The variation was not included in GWAS, 1000g, ESP, GnomeAD, ExAC and HGMD databases. According to ACMG guidelines, the variation was pathogenic. The mutation was predicted to lead to the production of a truncated protein. This mutation co-segregated with disease phenotypes and was not detected in unaffected members.  Conclusion A novel insertion mutation of FOXC1 gene c.1043_1044insGGCGCTC (p.Tyr353fs) was the cause of ARS in this family. At the same time, this is also the first report of ARS patients with leukoencephalopathy and cutaneous amyloidosis, extending the genotype and phenotype spectrum of the disease. (Ophthalmol CHN, 2024, 33: 187-192)

Key words: Axenfeld-Rieger syndrome, FOXC1 gene