Glaucoma (developmental)

Gene: FOXD3

Red List (low evidence)

Comment on list classification: As the evidence for the association of FOXD3 gene with eye disorder is disputed, this gene is demoted to red rating.

Created: 16 Oct 2025, 2:10 p.m. | Last Modified: 16 Oct 2025, 2:10 p.m.

Panel Version: 1.46

Monoallelic variants in FOXD3 gene have been associated with aniridia (MONDO:0019172) with 'Disputed' rating by the Glaucoma and Neuro-Ophthalmology expert panel in ClinGen (https://search.clinicalgenome.org/CCID:004877)

Although there are four unrelated families reported with anterior segment dysgenesis/Peters anomaly/aniridia and identified with four different variants in FOXD3 gene from one publication (PMID:22815627), all four variants are found at high population frequencies in gnomAD v4.1.0. In addition, there are neither any further reports of published human cases or nor any functional evidence or animal models in support of the association of this gene with this phenotype.

This gene has been associated with 'FOXD3-related anterior segment dysgenesis' phenotype on the Eye panel of Gene2Phenotype with 'limited' rating. However, this gene is not associated with any relevant eye phenotype in OMIM (last accessed on 16 October 2025).

Created: 16 Oct 2025, 2:08 p.m. | Last Modified: 16 Oct 2025, 2:08 p.m.

Panel Version: 1.45

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
aniridia, MONDO:0019172

Publications

• 22815627

Red List (low evidence)

Variants reported in PMID 22815627 have population frequencies out of keeping for monogenic disorders: p.Thr16Met is present in 87 individuals in gnomad, p.Pro120Leu is present in 1, p.Asn173His is present in 24, p.Arg273_Gly276dup is present in 152. Also note some of the variants were present in unaffected parents etc.

Created: 2 Aug 2020, 8:32 a.m. | Last Modified: 2 Aug 2020, 8:32 a.m.

Panel Version: 1.8

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Anterior segment dysgenesis; Peters anomaly; Glaucoma

Publications

• 22815627

Green List (high evidence)

DB Kloss et al. 2012: Five families with anterior segment disorders. Reported variants are missense

Created: 19 Jun 2019, 3:32 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
aniridia; Peters anomaly; Anterior segment dysgenesis

Publications

• 22815627

Mode of pathogenicity
Other - please provide details in the comments

Green List (high evidence)

Comment on list classification: Demoted from Green to Amber. Based on the expert reviews, this gene has been demoted from Green to Amber until new evidence is available.

Created: 16 Apr 2021, 3:02 p.m. | Last Modified: 16 Apr 2021, 3:02 p.m.

Panel Version: 1.34

Submitted on behalf of Professor Nicola Ragge (Wessex and West Midlands GLH). DB Kloss et al. 2012: Five families with anterior segment disorders. Reported variants are missense

Created: 17 Apr 2019, 3:30 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
aniridia; Peters anomaly; Anterior segment dysgenesis

Publications

• 22815627

Mode of pathogenicity
Other - please provide details in the comments

Red List (low evidence)

Only a single report, with four variants in five patients with aniridia or Peters anomaly (glaucoma status uncertain). All four variants are present in gnomAD (between 24 and 226 alleles). Also not clear that they follow a Mendelian pattern of inheritance - in three instances where parents were genotyped, the same variant was present in an unaffected parent.

Created: 14 Nov 2017, 7:22 a.m.

Publications

• PMID: 22815627

Comment on list classification: Feedback from Arianna Tucci: please add as the phenotype includes glaucoma and also add to the corneal abnormalities, cataract and the anophthalmia/microphthalmia panels.

Created: 26 Apr 2017, 8:44 a.m.

Comment on list classification: Not found in OMIM, Gene2Phenotype or Orphanet. Only one publication found with a mention of glaucoma - PMID: 22815627 which identified variants in 5 probands from 5 different pedigrees with anterior segment dysgenesis phenotypes Peters anomaly or aniridia. Unsure whether this should be included on the glaucoma panel.

Created: 12 Apr 2017, 3:03 p.m.

I don't know

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Anterior segment dysgenesis

Variants in this GENE are reported as part of current diagnostic practice