Neuro-Ophthalmology Panel

Last modified: Mar 21, 2018


  • Is a 38 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion / diagnosis of nystagmus, optic atrophy or progressive external ophthalmoplegia.

Analysis methods

  • PLUS
  • SEQ


3-4 weeks

Number of genes


Test code


CPT codes

SEQ 81404
SEQ 81405
SEQ 81406
DEL/DUP 81479


The Blueprint Genetics Neuro-Ophthalmology Panel (test code OP1301):

  • Is a 38 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

ICD codes

Commonly used ICD-10 code(s) when ordering the Neuro-Ophthalmology Panel

ICD-10 Disease
H55.00 Nystagmus
H49.40 Progressive external ophthalmoplegia
H47.20 Optic atrophy

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

Neuro-ophthalmological disorders are a group of diseases that affect vision, control of eye movements, or pupillary reflexes. They include diseases restricted to the visual system and systemic diseases in which the neuro-ophthalmologic sign is accompanied by other neurological symptoms. Optic atrophy affects primarily the retinal ganglion cells and the nerve fiber layer of the retina leading to decreased visual acuity (see the description of the Optic Atrophy Panel for details). Congenital nystagmus is defined as conjugated, spontaneous and involuntary ocular oscillations that appear at birth or during the first three months of life. Binocular vision and color vision are normal and visual acuity is typically better than 6/12. Variants in the X-linked FRMD7 explain approximately 85% of patients with congenital nystagmus. Female mutation carriers can be affected. The prevalence of congenital nystagmus is estimated to be 1:3,000. Examples of syndromes associated with eye movement problems are ataxia with oculomotor apraxia type 1 and 2, caused by variants in APTX and SETX, respectively, and horizontal gaze palsy with progressive scoliosis caused by variants in ROBO3. Variants in TUBB3 are associated with an autosomal dominant strabismus syndrome called congenital fibrosis of the extraocular muscles. Mitochondrial diseases frequently manifest with neuro-ophthalmologic symptoms and signs. Progressive external ophthalmoplegia (PEO) is characterized by weakness of the eye muscles. The symptoms in PEO include drooping eyelids (ptosis) and weakness or paralysis of the muscles that move the eye (ophthalmoplegia), and in some cases skeletal muscle myopathy. Autosomal dominant PEO may be caused by variants in POLGSLC25A4, or C10orf2. Ophthalmoplegia may also be associated with mitochondrial DNA depletion syndromes, which are a genetically and clinically heterogeneous group of autosomal recessive disorders.

Genes in the Neuro-Ophthalmology Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ACO2 Optic atrophy, Infantile cerebellar-retinal degeneration AR 13 13
ANTXR1 Hemangioma, capillary infantile, susceptibility to, Growth retardation, alopecia, pseudoanodontia, and optic atrophy (GAPO syndrome) AD/AR 6 11
APTX Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia AR 14 40
C10ORF2 Perrault syndrome, Mitochondrial DNA depletion syndrome AR 37
C12ORF65 Spastic paraplegia, Combined oxidative phosphorylation deficiency AR 10 10
CHN1 Duane retraction syndrome 2 AD 10 11
CISD2* Wolfram syndrome 2 AR 2 4
FDXR Auditory neuropathy and optic atrophy AR 4
FRMD7 Nystagmus, infantile periodic alternating XL 14 90
GPR143 Nystagmus, congenital, Ocular albinism XL 19 148
HESX1 Septooptic dysplasia, Pituitary hormone deficiency, combined AR/AD 11 26
KIF21A Fibrosis of extraocular muscles, congenital 1 AD 9 15
MFN2 Hereditary motor and sensory neuropathy, Charcot-Marie-Tooth disease AD/AR 52 218
NDUFS1 Mitochondrial complex I deficiency AR 22 25
NR2F1 Bosch-Boonstra optic atrophy syndrome AD 18 28
OPA1 Optic atrophy AD/AR 80 372
OPA3 Optic atrophy, 3-methylglutaconic aciduria AD/AR 8 15
OTX2 Microphthalmia, syndromic, Pituitary hormone deficiency, combined, Retinal dystrophy, early-onset, and pituitary dysfunction AD 17 65
PAX6 Aniridia, cerebellar ataxia, and mental retardation (Gillespie syndrome), Keratitis, Coloboma, ocular, Cataract with late-onset corneal dystrophy, Morning glory disc anomaly, Foveal hypoplasia, Aniridia, Optic nerve hypoplasia, Peters anomaly AD 106 473
PHOX2A Fibrosis of extraocular muscles, congenital, 2 AR 3 5
POLG POLG-related ataxia neuropathy spectrum disorders, Sensory ataxia, dysarthria, and ophthalmoparesis, Alpers syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome AD/AR 92 274
PRPS1* Deafness, Phosphoribosylpyrophosphate synthetase I superactivity, Arts syndrome, Charcot-Marie-Tooth disease, X-linked recessive, 5, Nonsyndromic sensorineural deafness, 2, X-linked XL 22 27
ROBO3 Gaze palsy, horizontal, with progressive scoliosis AR 15 35
RRM2B Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome AD/AR 41 40
RTN4IP1 Optic atrophy 10 with or without ataxia, mental retardation, and seizures AR 2 2
SALL4 Acro-renal-ocular syndrome, Duane-radial ray/Okohiro syndrome AD 17 50
SETX Ataxia with oculomotor apraxia, Amyotrophic lateral sclerosis, juvenile, Spinocerebellar ataxia AD/AR 27 190
SLC25A4 Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome AD/AR 12 13
SLC25A46 Neuropathy, hereditary motor and sensory, type VIB AR 12 13
SLC38A8 Foveal hypoplasia 2 AR 11 11
SOX2* Microphthalmia, syndromic AD 25 99
SPG7 Spastic paraplegia AR 53 104
TIMM8A* Mohr-Tranebjaerg syndrome, Jensen syndrome, Opticoacoustic nerve atrophy with dementia XL 10 21
TK2 Mitochondrial DNA depletion syndrome AR 38 45
TMEM126A Optic atrophy AR 2 1
TUBB3* Fibrosis of extraocular muscles, congenital, Cortical dysplasia, complex, with other brain malformations AD/AR 27 24
TYMP Mitochondrial DNA depletion syndrome AR 85 94
WFS1 Wolfram syndrome, Deafness AD/AR 65 343

* Some, or all, of the gene is duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ANTXR1 Chr2:69472345 c.1435-12A>G NM_032208.2
FRMD7 ChrX:131228285 c.285-118C>T NM_194277.2
GPR143 ChrX:9711844 c.659-131T>G NM_000273.2
GPR143 ChrX:9708630 c.885+748G>A NM_000273.2
OPA1 Chr3:193374829 c.2179-40G>C NM_130837.2
OPA1 Chr3:193335986 c.610+360G>A NM_130837.2
OPA1 Chr3:193335990 c.610+364G>A NM_130837.2
PAX6 Chr11:31685945 c.*125537G>T NM_000280.4 rs606231388
PAX6 Chr11:31828474 c.-128-1G>T NM_000280.4
PAX6 Chr11:31832374 c.-129+2T>A NM_000280.4
PAX6 Chr11:31828396 c.-52+1G>A NM_000280.4
PAX6 Chr11:31816377 c.524-41T>G NM_000280.4
TIMM8A ChrX:100601671 c.133-23A>C NM_004085.3 rs869320666
WFS1 Chr4:6271704 c.-43G>T NM_006005.3

Added and removed genes from the panel

Genes added Genes removed

Test strength

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • 1479 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations

Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

The Blueprint Genetics neuro-Ophthalmology panel covers classical genes associated with Mohr-Tranebjaerg syndrome, nystagmus, progressive external ophthalmoplegia, nystagmus 1, congenital, X-linked, ataxia – oculomotor apraxia, Acro-renal-ocular syndrome, horizontal gaze palsy with progressive scoliosis, Wolfram syndrome, septo-optic dysplasia and optic atrophy. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
The performance presented above reached by WES with the following coverage metrics
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%


The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.