OPTN

Inheritance Pattern: AD

Disease ID:MONDO:0007665

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013264

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013264

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: SD

Disease ID:MONDO:0013264

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0013264

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011693

Submitter: ClinGen

Optineurin was first identified as a binding partner of an adenoviral E3-14.7K protein and named as “FIP2“ (14.7-interacting protein) (Li et al. 1998, PMID: 9488477). Because optineurin has a strong homology to NF-kappa-B essential molecule (NEMO), it was also named as NRP (NEMO-related protein (Schwamborn et al. 2000, PMID:10807909). Through linkage study of a large family with a classical form of normal-tension open angle glaucoma, an adullt-onset POAG locus (GLC1E) was mapped to 10p15-p14 region (Sarfarazi et al. 1998, PMID: 9497264). Subsequently based on its physical location and its expression in retina, a candidate gene was identified and a heterozygous missense mutation [Glu50 > Lys (E50K)] was detected in the original GLC1E family and proved to be a recurrent mutation associated with hereditary primary open-angle glaucoma with normal intraocular pressure (OMIM:602432, Rezaie et al. 2002, PMID: 11834836). It was desigated as the *OPTN* (for optineurin, “optic neuropathy inducing” protein) (PMID: 11834836). *OPTN* variants have been identified in patients with glaucoma and patients with amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia. It appears that different types of *OPTN* variants are associated with specific diseases. The *OPTN* p.Glu50Lys variant, for example, has only been identified in patients with normal tension glaucoma (PMID: 11834836, 16988596, 12920093, 17293779, 14597044), while an ALS associated variant *OPTN* c.166+349_370-945del (aka *OPTN*, EX5DEL) has only been found in patients with ALS and not in patients with glaucoma. The *OPTN* c.381_382insAG variant is an exception in that it was detected in patients with glaucoma (PMID: 11834836, 17293779) and in patients with ALS (PMID: 21220178, 26740678). However, this variant is common in some populations, suggesting it is a founder mutation. There is limited functional evidence to support its association to glaucoma. Over 10 *OPTN* variants have been reported in patients with glaucoma. However, only the p.Glu50Lys (E50K) variant showed evidence, including genetic and experimental evidences, as a recurrent pathogenic variant associated with normal tension glaucoma with autosomal dominant inheritance. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance and molecular mechanism were found to be distinct between patients with normal tension glaucoma (monoallelic disruption of *OPTN* function) and ALS (biallelic loss of *OPTN* function). The lack of phenotypic overlap between the two diagnoses provided further support to curate normal tension glaucoma cases caused by *OPTN* variants as a separate disease entity, referred to as *OPTN*-related normal tension glaucoma. In summary, *OPTN* is definitively associated with normal tension glaucoma. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on November 17th, 2022 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0013264

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

Inheritance Pattern: SD

Disease ID:MONDO:0013264

Submitter: ClinGen

*OPTN* was first reported in relation to semi-dominant amyotrophic lateral sclerosis (ALS) type 12 in 2010 through homozygosity mapping of 6 Japanese individuals from consanguineous families where two different homozygous null variants and one heterozygous missense variant were discovered (Maruyama et al., PMID: 20428114). ALS is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brainstem and spinal cord, resulting in fatal paralysis. *OPTN* encodes for optineurin, a multiple domain protein ubiquitously expressed in many tissues, including the brain, skeletal muscle, and the eye. It plays important roles in vesicular trafficking, Golgi maintenance, secretion, receptor recycling, and as an autophagy receptor. It also influences the innate immune response by negatively regulating the NF-κB pathway. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in phenotypic variability and a difference in the types of variants seen in autosomal dominant open angle glaucoma and subtype normal tension glaucoma. Therefore, the following disease entities have been split into multiple disease entities: ALS 12 (OMIM:613435), primary open angle glaucoma (OMIM: 137760) and susceptibility to normal tension glaucoma (OMIM:606657). 40 variants (missense, nonsense, frameshift, large deletions) that have been reported in 43 probands in 19 publications (PMIDs: 2042814, 26203661, 29558868, 33727253, 34272080, 26740678, 21217154, 21074290, 21220178, 21802176, 21852022, 21613650, 22402017, 23062601, 25382069, 25588603, 26503823, 27534431, 31838784) are included in this curation. The strongest evidence for optineurin’s role as a causative gene for ALS is recessive loss of function variants, which appear to result in a more severe phenotype; reported monoallelic loss of function and missense variants provide some evidence but may pose more of a risk to develop disease. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by experimental evidence including expression studies (PMIDs: 20428114, 21825243), protein interaction (PMID: 23178947), functional alterations in non-patient cells (PMIDs: 25859013, 23178947, 34258561, 23721573, 30519240) animal models (PMIDs: 23178947, 27493188) and rescue experiments in vitro (PMID: 23721573). In summary, *OPTN* is definitively associated with semi-dominant ALS12. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld overtime. This classification was approved by the ClinGen ALS GCEP on May 10, 2022 (SOP Version 8).

Inheritance Pattern: AD

Disease ID:MONDO:0007665

Submitter: Labcorp Genetics (formerly Invitae)