1. NGS panel - Genetic testing for optic atrophy

Optic atrophy

August 21, 2017

Clinical features

Optic atrophy (OPA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing severe visual loss, typically starting during the first decade of life. The disease affects primarily the retinal ganglion neurons and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the deeper brain visual centers. The prevalence of the disease varies from 1/10,000 in Denmark due to a founder effect, to 1/30,000 in the rest of the world 1, 2. Optic atrophy is also known as dominant optic atrophy or Kjer’s Optic Atrophy, named after the Danish ophthalmologist Dr. Poul Kjer who was the first to describe the disease in the Danish population 1, 4.

Optic atrophy is also a feature of mitochondriopathy, as the genes responsible for OPA encode proteins ubiquitously expressed in mitochondria and associated to its inner membrane. Thus, OPA can be not only an isolated ophthalmological and neurological disease, but it can also be syndromic and include extra-ocular symptoms.

The diagnosis of OPA is based on a combination of clinical findings, electrophysiological studies, family history, and molecular genetic testing, and it is diagnosed in individuals with the following:

  • Bilateral symmetric vision loss
  • Optic nerve paleness (cardinal sign of optic nerve degeneration)
  • Visual field defect
  • Color vision defect, often described as acquired blue-yellow loss (tritanopia)
  • Childhood onset (first decade of life) 3

Electrophysiological recordings showed that visual-evoked responses in affected individuals characteristically demonstrate diminished amplitudes and prolonged latencies 3. Also, the pattern of electroretinogram recordings is abnormal in all patients affected with OPA.

The syndromic form of optic atrophy is accompanied by extra-ophthalmogic findings, including sensorineural hearing loss, ataxia, myopathy, ophtalmophlegia, and others. Mental abnormalities were identified in ~10’% of those affected 4. Syndromic forms of OPA account for up to 20% of all optic atrophies, with extra-ocular signs raging from mild to severe.

Optic atrophy is a clinically and genetically heterogeneous disorder. However, the majority of suspected hereditary optic neuropathy patients (>60%) 5 harbor pathogenic mutations within the OPA1 gene, and ~3% have mutations in the OPA3 gene 8. A broad spectrum of OPA1 pathogenic variants (>370) have been reported to date 5. The OPA1 pathogenic variants are distributed throughout the coding sequence of the gene, but most commonly they are localized in exons 8-16 encoding the GTPase domain of the protein.

Several different pathogenic variants in OPA1 have been reported in individuals with both optic atrophy and hearing loss: p.Arg445His, p.Gly401Asp, p.Leu243Ter, c.983A>G, p.Ile463_Phe464dup, p.Gln437Arg, and p.Ala357LeufsTer4 6.

Furthermore, pathogenic variants causing OPA with cerebellar ataxia, high myopia, spastic paraplegia, or other extra-ocular findings have been reported 7. Autosomal dominant optic atrophy-3 (OPA3), also known as optic atrophy and cataracts, is caused by heterozygous mutations in the OPA3 gene. Optic atrophy type 3 is characterized by classical OPA clinical findings together with the increased urinary excretion of (3-MGC) and 3-methylglutaric acid (3-MGA). Also, methylglutaconic aciduria type III (MGCA3), also known as optic atrophy plus syndrome, is an allelic disorder with similar but more severe features. The mutation c.143-1G>C accounts for 100% of OPA3 pathogenic variants in the Iraqi Jewish population 8. The pathogenic variant c.320_337del, found in an individual of Turkish-Kurdish origin with OPA3-related 3-methylglutaconic aciduria, is the first pathogenic variant found to date in an individual of non-Iraqi Jewish origin 9. The nonsense variant c. 415C>T (p.Gln139Ter), found in the homozygous state in an individual of Indian origin with OPA3-related 3-methylglutaconic aciduria, is the second pathogenic variant found to date in an individual of non-Iraqi Jewish origin 10. Genetic testing for the (most common) OPA3 variants targets the vast majority of OPA3 affected individuals.

Optic nerve degeneration and optic atrophy are present in many disorders in which mitochondrial impairment is the underlying cause for the degeneration of retinal cells. In addition to OPA-genes, mutations in WFS1 and MFN2 cause optic atrophy inherited in an autosomal dominant manner, mutations in AUH, C12orf65, NDUFS1, POLG, SPG7 and TMEM126A are inherited in an autosomal recessive manner, and mutations in TIMM8A are inherited in an X-linked manner. An overview of genes associated with optic atrophy is listed in the table.


Overview of genes and associated optic atrophy subtypes

Gene
(OMIM)
Inheritance
(chr.locus)
Clinical features Associated/allelic disorders (OMIM)
ACO2
(100850)
AR
(22q13.2)
Infantile onset optic atrophy and retinal degeneration, severe truncal hypotonia, athetosis, seizures, psychomotor retardation Optic atrophy 9 (616289), Infantile cerebellar-retinal degeneration (614559)
AFG3L2
(604581)
AD, AR
(18p11.21)
Young-adult onset, nystagmus, and ophthalmoparesis, slowly progressive gait and limb ataxia, dysarthria, hyperreflexia Spastic ataxia 5, autosomal recessive (614487); Spinocerebellar ataxia 28 (610246)
C12ORF65
(613541)
AR
(12q24.31)
Infantile onset of failure to thrive, psychomotor regression, ataxia, ptosis, nystagmus, severe optic atrophy, decreased vision, ophthalmoplegia Combined oxidative phosphorylation deficiency 7 (613559); Spastic paraplegia 55, autosomal recessive (615035)
CISD2
(611507)
AR
(4q24)
Diabetes insipidus, diabetes mellitus, optic atrophy and deafness, defective platelet aggregation Wolfram syndrome 2 (604928)
MFN2
(608507)
AD, AR
(1p36.22)
Early onset of lower limbs axonal, peripheral neuropathy, postural tremor, optic atrophy Charcot-Marie-Tooth disease, axonal, type 2A2A (609260); Charcot-Marie-Tooth disease, axonal, type 2A2B (617087); Hereditary motor and sensory neuropathy VIA (601152)
NR2F1
(132890)
AD
(5q15)
Delayed development, intellectual disability and optic atrophy Bosch-Boonstra-Schaaf optic atrophy syndrome (615722)
OPA1
(605290)
AD
(3q29)
Childhood onset bilateral optic nerve pallor, decreased visual acuity, hearing loss, ophthalmoplegia, muscle cramps, hyperreflexia and ataxia Optic atrophy 1 (165500); Optic atrophy plus syndrome (125250)
OPA3
(165300)
AD
(19q13.32)
Bilateral early onset optic atrophy, choreoathetoid movement disorder, cerebellar dysfunction, cognitive impairment, cataract Optic atrophy 3 with cataract (165300); 3-Methylglutaconic aciduria type III (258501); Behr syndrome (210000); Mitochondrial DNA depletion syndrome 14 (616896)
RTN4IP1
(610502)
AR
(6q21)
Bilateral optic neuropathy, nystagmus, ataxia, mental retardation and seizures Optic atrophy 10 with or without ataxia, mental retardation, and seizures (616732)
SLC25A46
(610826)
AR
(5q22.1)
Early-onset optic atrophy, progressive visual loss, peripheral axonal sensorimotor neuropathy, ataxia, dysmetria and myoclonus Neuropathy, hereditary motor and sensory, type VIB (616505)
SPG7
(602783)
AD, AR
(16q24.3)
Bilateral progressive lower limb weakness and spasticity, abnormal gait, hyperreflexia sphincter disturbances, spastic dysarthria, dysphagia, ataxia, pale optic disks, nystagmus, strabismus, decreased hearing, scoliosis Spastic paraplegia 7, autosomal recessive (607259)
TIMM8A
(300356)
XLR
(Xq22.1)
Young-adult onset of progressive deafness, dystonia and optic atrophy Mohr-Tranebjaerg syndrome (304700)
TMEM126A
(612988)
AR
(11q14.1)
Juvenile-onset optic atrophy, bilateral visual acuity deficiency, optic disc pallor and central scotoma Optic atrophy 7 (612989)
WFS1
(606201)
AD, AR
(4p16.1)
Diabetes mellitus, optic atrophy, diabetes insipidus and deafness, myopathy, ataxia, and neuropathy Wolfram syndrome (222300); Cataract 41 (116400); Deafness, autosomal dominant 6/14/38 (600965); Wolfram-like syndrome (614296)

To date, there is no preventative or curative treatment for optic atrophy. However, symptomatic treatment that is initiated before the development of optic atrophy can be helpful in saving useful vision. The role of intravenous steroids was proven as helpful in cases with optic neuritis. Early diagnosis and prompt treatment can help patients with progressive and severe neuropathies. Development of therapeutic approaches based on stem cell therapy and gene therapy are in progress.

CENTOGENE offers full gene sequencing and deletion/duplication analysis for the Optic atrophy panel (genes: ACO2, AFG3L2, C12ORF65, CISD2, MFN2, NR2F1, OPA1, OPA3, RTN4IP1, SLC25A46, SPG7, TIMM8A, TMEM126A, WFS1).


Differential diagnosis

The differential diagnosis of optic atrophy-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Leber hereditary optic neuropathy, caused by mutations in mtDNA (most commonly: m.11778G>A, m.14484T>C, m.3460G>A)
  • Wolfram´s syndrome, caused by mutations in WF1 or CISD2
  • Friedreich ataxia, caused by mutations in the FXN gene
  • Deafness-dystonia-optic neuronopathy syndrome, caused by mutations in the TIMM8A gene
  • Inborn errors of metabolism with 3-methylglutaconic aciduria
  • Acquired optic neuropathy caused by nutritional deficiencies, toxic exposures or certain medications.

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology.This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for optic atrophy using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Optic atrophy panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the optic atrophy panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.


Referral reasons

The following individuals are candidates for optic atrophy testing:

  • Individuals with a family history of optic atrophy and presentation of the most common symptoms
  • Individuals without a positive family history of optic atrophy, but with symptoms resembling the disease
  • Individuals with a negative but suspected family history of optic atrophy, in order to perform proper genetic counseling.

Test utility

Sequencing, deletion/duplication of the optic atrophy panel genes should be performed in all individuals suspected of having Maple syrup urine disease and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the optic atrophy and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.


More information on CENTOGENE´s Optic atrophy panel can be found in our genetic test catalogue.