Structural eye disease

Gene: OPTN

Red List (low evidence)

Structural eye disease panel scope includes congenital/developmental glaucoma. Congenital glaucoma is considered when diagnosed up to 3 years of age, with the juvenile onset sub-category considered up to between 30 and 40 years (PMID 34536459 (2021)). OPTN is an established risk factor gene for autosomal dominant normal tension glaucoma (NTG), with a Definitive ClinGen classification. Multiple studies report monoallelic OPTN variants in adult-onset NTG/open angle glaucoma (PMID 11834836, 2022), with the strongest evidence supporting the recurrent p.Glu50Lys (E50K) variant. Heterozygous E50K causes earlier-onset (mean ~41 years), more severe adult NTG but shows incomplete penetrance, with unaffected carriers described aged 23-58 years (PMID 16043855, 2005). This adult-onset NTG phenotype falls outside R36 scope. Registry data further confirm OPTN variants associate with early onset NTG, clustering in the 3rd-decade, not congenital/childhood/developmental glaucoma or anterior segment anomalies (PMID 33892047, 2021).

Evidence in childhood/congenital phenotypes is limited. One juvenile open angle glaucoma (JOAG) patient (onset aged 17 years) carried heterozygous OPTN H486R (classified VUS via clinvar), with no segregation and limited screening other glacuoma-related genes (PMID 15326130, 2004). A 67-patient JOAG cohort, in which MYOC, OPTN, NTF4, WDR36, CYP1B were screened, identified two heterozygous OPTN variants- R329G (onset aged 27 years) and L494W (onset aged 33 years). L494W was identified in an unrelated frontotemporal dementia (FTD) patient without glaucoma, where functional validation was inconclusive or did not demonstrate significant impact (PMID 29540704, 2018; PMID 38872230, 2024).

A single congenital glaucoma family is described in (PMID 37530275, 2023), comprising a proband with primary congenital glaucoma (PCG) (heterozygous, onset aged 2 years), his sister with PCG (homozygous, onset aged 2.5 years), and their mother with juvenile open angle glaucoma (JOAG) (heterozygous, onset aged 18 years), all carrying p.G538E, supported primarily by in silico prediction. This single family, with mixed inheritance and co-segregating JOAG, does not meet the ≥3 unrelated cases threshold for a congenital phenotype.

Conclusions: A red rating is recommended for R36 (structural eye disease): the established phenotype is predominantly adult-onset NTG open angle glaucoma, juvenile/congenital case evidence is sparse and unreplicated and implicates mostly early-onset (not childhood), and functional/segregation support is sparse or supports pathogenicity mainly of known incomplete penetrance risk variants (OPTN E50K). Further input is sought via NHS review regarding the applicability of this gene.

Created: 30 Jul 2026, 1:09 p.m. | Last Modified: 30 Jul 2026, 1:09 p.m.

Panel Version: 5.7

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Glaucoma 1, open angle, E, OMIM:137760; {Glaucoma, normal tension, susceptibility to}, OMIM:606657

Publications

• 34536459
• 16043855
• 33892047
• 15326130
• 38872230
• 37530275

Green List (high evidence)

Multiple studies reporting OPTN as cause of autosomal dominant juvenile glaucoma, both open angle and normal tension types, in more than 3 unrelated families. Some patients diagnosed under 18 years old. One report (PMID: 37530275) of OPTN as causative for both juvenile and congenital glaucoma in a single family, although only limited screening of other developmental genes undertaken.

Created: 17 Jun 2026, 1:18 p.m. | Last Modified: 17 Jun 2026, 1:18 p.m.

Panel Version: 5.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Juvenile open angle glaucoma; Juvenile normal tension glaucoma; HP:0001087 developmental glaucoma; HP:0012108 open angle glaucoma; HP:0000501 glaucoma

Publications

• PMID: 37530275
• 15326130
• 29540704
• 16043855
• 33892047

Red List (low evidence)

glaucoma gene, can't find any evidence that it is associated with structural eye disease. Glaucoma seems adult-onset

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

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Glaucoma 1, open angle, E; 137760

Publications

• 11834836

Red List (low evidence)

Submitted on behalf of Professor Nicola Ragge (Wessex and West Midlands GLH). glaucoma gene, can't find any evidence that it is associated with structural eye disease. Glaucoma seems adult-onset

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

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Glaucoma 1, open angle, E, 137760

Publications

• 11834836