- 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.
Number of genes38
CPT codesSEQ 81404
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
Commonly used ICD-10 code(s) when ordering the Neuro-Ophthalmology Panel
|H49.40||Progressive external ophthalmoplegia|
- 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 POLG, SLC25A4, 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
|ACO2||Optic atrophy, Infantile cerebellar-retinal degeneration||AR||16||13|
|ANTXR1||Hemangioma, capillary infantile, susceptibility to, Growth retardation, alopecia, pseudoanodontia, and optic atrophy (GAPO syndrome)||AD/AR||6||13|
|APTX||Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia||AR||14||42|
|C10ORF2||Perrault syndrome, Mitochondrial DNA depletion syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 3||AR||36||77|
|C12ORF65||Spastic paraplegia, Combined oxidative phosphorylation deficiency||AR||10||11|
|CHN1||Duane retraction syndrome 2||AD||10||11|
|CISD2*||Wolfram syndrome 2||AR||2||4|
|FDXR||Auditory neuropathy and optic atrophy||AR||5||17|
|FRMD7||Nystagmus, infantile periodic alternating||XL||15||90|
|GPR143||Nystagmus, congenital, Ocular albinism||XL||22||148|
|HESX1||Septooptic dysplasia, Pituitary hormone deficiency, combined||AR/AD||14||26|
|KIF21A||Fibrosis of extraocular muscles, congenital 1||AD||9||15|
|MFN2||Hereditary motor and sensory neuropathy, Charcot-Marie-Tooth disease||AD/AR||59||220|
|NDUFS1||Mitochondrial complex I deficiency||AR||22||27|
|NR2F1||Bosch-Boonstra optic atrophy syndrome||AD||20||31|
|OPA1||Optic atrophy, Optic atrophy 1, Optic atrophy with or without deafness, Ophthalmoplegia, myopathy, ataxia, and neuropathy, Behr synrome, Mitochondrial DNA depletion syndrome 14||AD/AR||97||387|
|OPA3||Optic atrophy, 3-methylglutaconic aciduria||AD/AR||9||15|
|OTX2||Microphthalmia, syndromic, Pituitary hormone deficiency, combined, Retinal dystrophy, early-onset, and pituitary dysfunction||AD||21||68|
|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||130||518|
|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||90||280|
|PRPS1*||Deafness, Phosphoribosylpyrophosphate synthetase I superactivity, Arts syndrome, Charcot-Marie-Tooth disease, X-linked recessive, 5, Nonsyndromic sensorineural deafness, 2, X-linked||XL||27||31|
|ROBO3||Gaze palsy, horizontal, with progressive scoliosis||AR||16||38|
|RRM2B||Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome||AD/AR||42||41|
|RTN4IP1||Optic atrophy 10 with or without ataxia, mental retardation, and seizures||AR||2||12|
|SALL4||Acro-renal-ocular syndrome, Duane-radial ray/Okohiro syndrome||AD||19||55|
|SETX||Ataxia with oculomotor apraxia, Amyotrophic lateral sclerosis, juvenile, Spinocerebellar ataxia||AD/AR||35||194|
|SLC25A4||Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome||AD/AR||12||15|
|SLC25A46||Neuropathy, hereditary motor and sensory, type VIB||AR||12||13|
|SLC38A8||Foveal hypoplasia 2||AR||11||12|
|TIMM8A*||Mohr-Tranebjaerg syndrome, Jensen syndrome, Opticoacoustic nerve atrophy with dementia||XL||10||21|
|TK2||Mitochondrial DNA depletion syndrome||AR||38||45|
|TUBB3*||Fibrosis of extraocular muscles, congenital, Cortical dysplasia, complex, with other brain malformations||AD/AR||27||25|
|TYMP||Mitochondrial DNA depletion syndrome||AR||85||94|
|WFS1||Wolfram syndrome, Deafness, Wolfram-like syndrome, autosomal dominant, Deafness, autosomal dominant 6/14/38, Cataract 41||AD/AR||68||351|
* 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|
Added and removed genes from the panel
|Genes added||Genes removed|
|ACO2 ANTXR1 CHN1 CISD2 FDXR KIF21A NR2F1 PHOX2A PRPS1 RTN4IP1 SLC25A46 SLC38A8|
Test strengthThe 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
- ~1,500 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
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.
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.