- Is a 8 gene panel that includes assessment of non-coding variants
Is ideal for patients with a clinical suspicion of neurofibromatosis type I and related disorders.
The Blueprint Genetics Neurofibromatosis Panel (test code MA1501):
Commonly used ICD-10 code(s) when ordering the Neurofibromatosis Panel
|Q85.00||Neurofibromatosis type 1|
|Q85.00||Neurofibromatosis type 2|
- Blood (min. 1ml) in an EDTA tube
- Extracted DNA, min. 2 μg in TE buffer or equivalent
- Saliva (Oragene DNA OG-500 kit/OGD-500 or OG-575 & OGD-575)
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. Read more about our sample requirements here.
Neurofibromatosis type 1 and 2 are autosomal dominant conditions. The panel is efficient in differential diagnosis of neurofibromatosis and related disorders, such as Legius syndrome (SPRED1), Noonan with multiple lentigines syndrome (aka LEOPARD syndrome; PTPN11 and RAF1), and familial schwannomatosis (SMARCB1). Neurofibromatosis type 1 (NF1) is clinically characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50% of patients. Less common but potentially more serious manifestations include plexiform neurofibromas, optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy. The clinical features are highly variable, even within the same family. NF1 is caused by heterozygous mutations in the NF1 gene, encoding neurofibromin. About half of the affected individuals have a de novo mutation. NF1 is relatively common inherited disorder, the prevalence is 1:3,000. Neurofibromatosis type 2 (NF2) is a tumour-prone disorder characterised by the development of multiple schwannomas and meningiomas. The hallmark of NF2 is the development of bilateral vestibular schwannomas leading to hearing loss, tinnitus or imbalance or a combination of the three symptoms. The other main tumors are schwannomas of the other cranial, spinal and peripheral nerves; meningiomas both intracranial (including optic nerve meningiomas) and intraspinal, and some low-grade central nervous system malignancies (ependymomas). Ophthalmic features, including reduced visual acuity and cataract are also prominent. Cutaneous features in NF2 are much more subtle than in NF1. About 70% of NF2 patients have skin tumours. NF2 is caused by mutations in the NF2 gene, and more than 50% of patients represent new mutations and as many as one-third are mosaic for the underlying disease-causing mutation. The prevalence of NF2 is 1:60,000. Some syndromes share similar clinical features with NF1 and NF2. Legius syndrome is a very rare condition charaterized by multiple café-au-lait macules with or without axillary or inguinal freckling. About 2% of patients fulfilling diagnostic criteria for NF1 are found to have the genetic mutation underlying Legius syndrome (SPRED1). Familial schwannomatosis is characterized by the development of multiple spinal, peripheral, and cranial-nerve schwannomas in the absence of vestibular schwannomas. It is inherited in an autosomal dominant manner and caused by mutations in SMARCB1. LEOPARD syndrome is a multisystem disorder involving the skin, skeletal and cardiovascular systems. The characteristic feature is brown skin spots called lentigines that are similar to freckles.
Genes in the Neurofibromatosis Panel and their clinical significance
|KIT||Gastrointestinal stromal tumor, Piebaldism||AD||79||116|
|KITLG||Hyperpigmentation with or without hypopigementation, familial progressive, Skin/hair/eye pigmentation, variation in, 7||AD||6||10|
|NF1*||Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndrome||AD||1157||2901|
|PTPN11||Noonan syndrome, Metachondromatosis||AD||135||140|
|RAF1||LEOPARD syndrome, Noonan syndrome, Dilated cardiomyopathy (DCM)||AD||45||53|
|SMARCB1||Schwannomatosis, Rhabdoid tumor predisposition syndrome, Coffin-Siris syndrome 3||AD||36||118|
* 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 Neurofibromatosis Panel
|Gene||Genomic location HG19||HGVS||RefSeq||RS-number|
- 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).
- 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).
- Low level mosaicism (variant with a minor allele fraction of 14.6% is detected with 90% probability)
- 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 neurofibromatosis panel covers classical genes associated with neurofibromatosis, neurofibromatosis type 1, neurofibromatosis type 2, schwannomatosis and Legius syndrome. 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 is orthogonal confirmation. Sequence variants classified as pathogenic, likely pathogenic and variants of uncertain significance
(VUS) are confirmed using bi-directional Sanger sequencing when they do not meet our stringent NGS quality metrics for a 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 (Plus analysis only).
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.
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.