Frontiers in medicine · 2026
Case Report: Novel FOXC1 variant c.311T>G (p.Ile104Ser) in a Chinese family with Axenfeld-Rieger syndrome.
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Lin Bin, Li Li, Li Dong-Kan
Аннотация
BACKGROUND: Juvenile-onset open-angle glaucoma (JOAG) is a heterogeneous early-onset glaucoma subtype. Axenfeld-Rieger syndrome (ARS) is an autosomal dominant disorder caused by FOXC1 variants, which may present with severe early-onset glaucoma and can be clinically mistaken for JOAG. This study aimed to determine the genetic cause and clarify the clinical diagnosis in a Chinese family initially diagnosed with JOAG.
METHODS: A 15-year-old male proband and his family members received detailed ophthalmic and systemic evaluations. Whole-exome sequencing was performed in the proband, and candidate variants were verified by Sanger sequencing. Bioinformatic tools were used to evaluate variant pathogenicity.
RESULTS: The proband and his elder sister initially presented with severe early-onset glaucoma and were diagnosed with JOAG at an outside hospital. After systemic evaluation, they were found to have anterior segment dysgenesis and characteristic facial features, including midface hypoplasia, hypertelorism, and saddle nose deformity, supporting a revised diagnosis of ARS. A novel heterozygous missense variant c.311T>G (p.Ile104Ser) in FOXC1 was identified. This variant was absent from the East Asian population in gnomAD and was predicted to be highly deleterious. It co-segregated with the disease phenotype and showed incomplete penetrance in the unaffected father.
CONCLUSION: We identified a novel FOXC1 variant responsible for ARS in a Chinese family. ARS-associated glaucoma can closely mimic JOAG, leading to initial misdiagnosis. The observation of incomplete penetrance in an unaffected carrier father underscores the phenotypic complexity of this disorder. Our findings expand the genotypic spectrum of FOXC1-related disorders and highlight the importance of systemic evaluation and genetic testing in patients with early-onset glaucoma.
METHODS: A 15-year-old male proband and his family members received detailed ophthalmic and systemic evaluations. Whole-exome sequencing was performed in the proband, and candidate variants were verified by Sanger sequencing. Bioinformatic tools were used to evaluate variant pathogenicity.
RESULTS: The proband and his elder sister initially presented with severe early-onset glaucoma and were diagnosed with JOAG at an outside hospital. After systemic evaluation, they were found to have anterior segment dysgenesis and characteristic facial features, including midface hypoplasia, hypertelorism, and saddle nose deformity, supporting a revised diagnosis of ARS. A novel heterozygous missense variant c.311T>G (p.Ile104Ser) in FOXC1 was identified. This variant was absent from the East Asian population in gnomAD and was predicted to be highly deleterious. It co-segregated with the disease phenotype and showed incomplete penetrance in the unaffected father.
CONCLUSION: We identified a novel FOXC1 variant responsible for ARS in a Chinese family. ARS-associated glaucoma can closely mimic JOAG, leading to initial misdiagnosis. The observation of incomplete penetrance in an unaffected carrier father underscores the phenotypic complexity of this disorder. Our findings expand the genotypic spectrum of FOXC1-related disorders and highlight the importance of systemic evaluation and genetic testing in patients with early-onset glaucoma.