FOXC1 variant in a family with anterior segment dysgenesis and normal-tension glaucoma

Lior Or*, Yaniv Barkana, Idan Hecht, Chen Weiner, Adi Einan-Lifshitz, Eran Pras

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Our study describes the glaucoma phenotype in a family with Axenfeld-Rieger syndrome (ARS) and a FOXC1 variant. Included were 20 subjects from a large three generation family of Jewish Indian ancestry. Subjects underwent a comprehensive ophthalmic examination including automated perimetry and optical coherence tomography. Eight subjects were available for molecular analysis which included whole genome sequencing on selected patients and Sanger sequencing for variant screening. Eleven patients demonstrated a wide spectrum of Axenfeld-Rieger anomaly signs and symptoms. These ranged from subtle angle abnormalities to remarkable anterior segment abnormalities such as corectopia, iris adhesions and strands. Among them, six had glaucoma and two were glaucoma suspects. Of the six subjects with glaucoma three had high-tension glaucoma and two had normal-tension glaucoma. Molecular analysis revealed a previously described pathogenic variant in the FOXC1 gene (c.378C > G p.I126M; rs104893958), in six affected patients which was not identified in two healthy siblings. Molecular analysis also revealed a PITX2 missense variant (c.28T > A p.L10M; rs755864040) which did not segregate with clinical findings and was considered likely benign. In conclusion, patients with ARS due to FOXC1 variants may present with glaucomatous optic nerve damage without apparent elevation in IOP. Normal-tension glaucoma is less commonly reported in individuals with ARS and a comprehensive glaucoma assessment may be warranted in these individuals even with normal IOP. These findings raise the possibility that glaucomatous damage associated with FOXC1 is not only due to high IOP.

Original languageEnglish
Article number108220
JournalExperimental Eye Research
StatePublished - Nov 2020


FundersFunder number
Claire and Amedee Maratier Institute for the Study of Blindness
Sackler Faculty of Medicine, Tel Aviv University
Shamir Medical Center , Israel and ‘Lirot’ Association
Shamir Medical Center, Israel
Visual Disorders
Claire and Amédée Maratier Institute for the Study of Blindness and Visual Disorders, Tel Aviv University
Sackler Faculty of Medicine, Tel-Aviv University


    • Anterior segment dysgenesis
    • Axenfeld-Rieger syndrome
    • Developmental glaucoma
    • FOXC1
    • Normal tension glaucoma


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