Submission Details

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).