OPA1

Inheritance Pattern: SD

Disease ID:MONDO:0800181

Submitter: PanelApp Australia

Inheritance Pattern: SD

Disease ID:MONDO:0800181

Submitter: ClinGen

The *OPA1* gene was first reported in relation to autosomal dominant optic atrophy 1 in 2000 (PMID: 11017079, PMID: 11017080). Cases with this diagnosis share the phenotype of optic atrophy and are characterized by other ocular features such as progressive visual loss, central scotoma, and color vision abnormalities, with pediatric onset and abnormal mitochondrial morphology. Subsequent reports have expanded the phenotypes of autosomal dominant *OPA1*-related cases to include an optic atrophy plus syndrome with additional extraocular features that can include progressive sensorineural hearing impairment, cognitive impairment, peripheral neuropathy, myopathy, ragged-red muscle fibers, and exercise-induced lactic acidemia, as well as multiple mitochondrial DNA deletions (PMID: 16158427, PMID: 18158317). Families have also emerged with members harboring homozygous or compound heterozygous *OPA1* variants, with those individuals exhibiting more severe effects than their relatives with monoallelic variants (PMID: 11440988, PMID: 25146916). Patients with biallelic *OPA1* variants have typically been diagnosed with Behr syndrome (PMID: 25012220, PMID: 25146916), while a subset of those receiving this diagnosis has been recognized as overlapping with the Leigh syndrome spectrum (PMID: 28494813, PMID: 28442211). These cases exhibit optic atrophy and other ocular features, as well as infantile onset of neurological symptoms (such as global developmental delay, ataxia, sensory axonal neuropathy, hypotonia, dysphagia, nystagmus, and seizures) and abnormalities of brain morphology (such as atrophy of structures such as the cerebellar vermis and caudate nucleus, and MRI hyperintensities in cerebral white matter and other regions). Additional features include metabolic symptoms (increased lactate in the serum and central nervous system, decreased activity of mitochondrial complexes, and depletion of mitochondrial DNA in muscle tissue), and digestive issues (such as episodic vomiting and chronic constipation). Some particularly severe homozygous cases with death in infancy have been diagnosed with mitochondrial DNA depletion syndrome 14 (PMID: 26561570). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the molecular mechanism (*OPA1* loss of function) was found to be consistent among patients with optic atrophy 1 (MIM#: 165500), optic atrophy plus syndrome (MIM#: 125250), mitochondrial DNA depletion syndrome 14 (MIM#: 616896), and Behr syndrome (MIM#: 210000), including the Leigh syndrome-like cases (MIM#: 256000). The phenotypic variability between them appears to represent a spectrum of disease rather than separate disease entities, with underlying mitochondrial dysfunction as a shared feature. Therefore, cases caused by inherited *OPA1* variants have been lumped into a single disease entity, referred to as *OPA1*-related optic atrophy with or without extraocular features (MONDO:0800181), with a semidominant mode of inheritance. Sixteen suspected pathogenic variants were scored as part of this curation (two nonsense, three frameshift, two affecting splicing, and nine missense), which have been collectively reported in eighteen probands in seven publications (PMID: 11017079, PMID: 11017080, PMID: 18158317, PMID: 25012220, PMID: 26561570, PMID: 28494813, PMID: 28442211). Nine of the probands scored in this curation harbored only one variant allele within the *OPA1* locus, while the other nine probands harbored biallelic *OPA1* variants. The mechanism of pathogenicity appears to be monoallelic or biallelic loss of *OPA1* function conferred by null and/or hypomorphic variants. One family with segregation evidence contributed to the scoring of the gene-disease relationship (PMID:11735024). The literature included more case-level evidence (PMID: 11440988, PMID: 16158427, PMID: 25146916) and segregation evidence (PMID: 11017079, PMID: 11017080), but their inclusion in this curation was not necessary to reach the maximum score for genetic evidence. This gene-disease association is also supported by biochemical evidence that OPA1 localizes to the mitochondrial inner membrane (PMID: 11038181) and functions as a GTPase (PMID: 15509649) to promote mitochondrial fusion (PMID: 11038181), to prevent mitochondrial network fragmentation (PMID: 12509422), and to control mitochondrial cristae shape to prevent cytochrome C release and apoptosis through the intrinsic pathway (PMID: 16839885). *OPA1* is ubiquitously expressed but exhibits its highest expression levels in ocular tissues (PMID: 30239781). Cellular models of OPA1 loss-of-function exhibit disorganization of cristae structure, enhanced apoptosis (PMID: 12509422), depletion of mitochondrial DNA, and mitochondrial respiratory chain deficiency (PMID: 1532158). A mouse model harboring a heterozygous null *Opa1* variant recapitulates human patient features such as progressive optic nerve abnormalities, reduced visual acuity, and fragmentation of the mitochondrial network (PMID: 17428816). Homozygous animals exhibit early embryonic lethality (PMID: 17428816), indicating that phenotypic severity across patients may correlate with the degree of retention of residual OPA1 function. Correction of an *OPA1* variant by CRISPR/Cas9 editing in induced pluripotent stem cells from a patient largely rescues their phenotypes of mitochondrial network fragmentation, bioenergetic defects, and susceptibility to apoptotic stimuli (PMID: 34589289). In summary, *OPA1* is definitively associated with *OPA1*-related optic atrophy with or without extraocular features. 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 curation represents an update of the previous curation of *OPA1* for Leigh syndrome. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel and the ClinGen Mitochondrial Diseases Gene Curation Expert Panel on September 21st, 2022 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0014820

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0008134

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0008858

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between OPA1 and Leigh syndrome spectrum (LSS) was evaluated using the ClinGen Clinical Validity Framework as of December 16, 2020. The OPA1 gene encodes a mitochondrial dynamin-like GTPase that localizes to the mitochondrial inner membrane and coordinates inner membrane fusion. Mitochondria are dynamic organelles constantly moving along the cell cytoskeleton and form functional networks in many cells. Mitochondria undergo frequent fusion and fission events, which allow formation of these networks. Defects in OPA1 lead to impaired mitochondrial fusion and dynamics. The OPA1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2017 (PMID: 28494813). Of note, variants in OPA1 are more frequently associated with autosomal dominant optic atrophy with or without additional multisystem features, or with Behr syndrome, characterized by optic atrophy and neurologic features and inherited in an autosomal recessive manner. Evidence supporting the relationship between OPA1 and LSS includes case-level data and experimental data. This curation included five unique variants identified in four cases from two publications (PMID: 28494813, 28442211). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, and animal models (PMIDs: 33092941, 18853439, 17428816). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 16, 2020 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0014820

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0007429

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0008858

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008134

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0003608

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0007429

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014720

Submitter: Orphanet