- Is a 74 gene panel that includes assessment of non-coding variants
Is ideal for patients with a clinical suspicion of leukodystrophy or leukoencephalopathy. The genes on this panel are included on the Comprehensive Epilepsy Panel.
The Blueprint Genetics Leukodystrophy and Leukoencephalopathy Panel (test code NE2001):
Commonly used ICD-10 code(s) when ordering the Leukodystrophy and Leukoencephalopathy Panel
- 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.
Leukodystrophies are heritable myelin disorders affecting the white matter of the central nervous system with or without peripheral nervous system myelin involvement. Leukodystrophies with an identified genetic cause may be inherited in an autosomal dominant, an autosomal recessive or an X-linked recessive manner. Genetic leukoencephalopathy is heritable and results in white matter abnormalities but does not necessarily meet the strict criteria of a leukodystrophy (PubMed: 25649058). The mainstay of diagnosis of leukodystrophy and leukoencephalopathy is neuroimaging. However, the exact diagnosis is difficult as phenotypes are variable and distinct clinical presentation can be present within the same family. Genetic testing is leading to an expansion of the phenotypic spectrum of the leukodystrophies/encephalopathies. These findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis.
Genes in the Leukodystrophy and Leukoencephalopathy Panel and their clinical significance
|ADAR||Dyschromatosis symmetrica hereditaria, Aicardi-Goutières syndrome||AD/AR||25||226|
|AIFM1||Deafness, Combined oxidative phosphorylation deficiency 6, Cowchock syndrome||XL||27||31|
|AP4B1||Spastic paraplegia 47, autosomal recessive||AR||17||18|
|AP4E1||Stuttering, familial persistent, 1, Spastic paraplegia 51, autosomal recessive||AR||7||15|
|AP4M1||Spastic paraplegia 50, autosomal recessive||AR||16||13|
|AP4S1*||Spastic paraplegia 52, autosomal recessive||AR||9||8|
|APOPT1||Mitochondrial complex IV deficiency||AR||4||5|
|ASPA||Aspartoacylase deficiency (Canavan disease)||AR||54||102|
|CLCN2||Leukoencephalopathy with ataxia, Epilepsy||AD/AR||30||36|
|COL4A1||Schizencephaly, Anterior segment dysgenesis with cerebral involvement, Retinal artery tortuosity, Porencephaly, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, Brain small vessel disease||AD||58||107|
|COX15||Leigh syndrome, Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency||AR||7||5|
|COX6B1||Mitochondrial complex IV deficiency||AR||2||3|
|CSF1R||Leukoencephalopathy, diffuse hereditary, with spheroids||AD||56||83|
|CTC1||Cerebroretinal microangiopathy with calcifications and cysts||AR||21||33|
|D2HGDH||D-2-hydroxyglutaric aciduria 1||AR||13||33|
|DARS||Hypomyelination with brainstem and spinal cord involvement and leg spasticity||AR||11||17|
|DARS2||Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation||AR||27||61|
|EARS2||Combined oxidative phosphorylation deficiency||AR||14||30|
|EIF2B1||Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy||AR||7||9|
|EIF2B2||Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy||AR||12||28|
|EIF2B3||Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy||AR||6||22|
|EIF2B4||Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy||AR||8||30|
|EIF2B5||Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy||AR||20||98|
|FOLR1||Cerebral folate deficiency||AR||10||28|
|FOXRED1||Leigh syndrome, Mitochondrial complex I deficiency||AR||15||8|
|GFM1||Combined oxidative phosphorylation deficiency||AR||19||19|
|GJC2||Spastic paraplegia, Lymphedema, hereditary, Leukodystrophy, hypomyelinating||AD/AR||26||57|
|HEPACAM||Megalencephalic leukoencephalopathy with subcortical cysts, remitting||AD/AR||12||26|
|HIBCH||3-hydroxyisobutryl-CoA hydrolase deficiency||AR||18||16|
|HSPD1*||Spastic paraplegia, Leukodystrophy, hypomyelinating||AD/AR||5||5|
|HTRA1||Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2 (CADASIL2), Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)||AD/AR||25||46|
|IBA57||Multiple mitochondrial dysfunctions syndrome 3, Spastic paraplegia 74, autosomal recessive||AR||14||23|
|LMNB1||Leukodystrophy, demyelinating, adult-onset, autosomal dominant||AD||2||35|
|LYRM7#||Mitochondrial complex III deficiency, nuclear type 8||AR||5||9|
|MARS2||Combined oxidative phosphorylation deficiency||AR||8||5|
|MLC1||Megalencephalic leukoencephalopathy with subcortical cysts||AR||39||108|
|MRPL44||Combined oxidative phosphorylation deficiency 16||AR||2||2|
|MTFMT||Combined oxidative phosphorylation deficiency 15||AR||15||16|
|NDUFAF5||Mitochondrial complex I deficiency||AR||8||12|
|NFU1||Multiple mitochondrial dysfunctions syndrome 1||AR||6||15|
|NOTCH3||Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Lateral meningocele syndrome||AD||87||364|
|NUBPL||Mitochondrial complex I deficiency||AR||9||10|
|PLP1||Spastic paraplegia, Pelizaeus-Merzbacher disease||XL||60||348|
|PSAP||Krabbe disease, atypical, Metachromatic leukodystrophy due to saposin-b deficiency, Combined saposin deficiency, Gaucher disease, atypical, due to saposin C deficiency||AR||18||26|
|PYCR2#||Leukodystrophy, hypomyelinating 10||AR||11||13|
|RARS||Leukodystrophy, hypomyelinating 9||AR||12||11|
|RNASET2||Leukoencephalopathy, cystic, without megalencephaly||AR||8||12|
|RNF216*||Cerebellar ataxia and hypogonadotropic hypogonadism (Gordon Holmes syndrome)||AR||10||14|
|SAMHD1||Aicardi-Goutières syndrome, Chilblain lupus 2||AD/AR||25||56|
|SCO1||Mitochondrial complex IV deficiency||AR||6||5|
|SDHAF1||Mitochondrial complex II deficiency||AR||4||6|
|SERAC1||3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome||AR||22||52|
|SNORD118||Leukoencephalopathy, brain calcifications, and cysts (Labrune syndrome)||AR||6||39|
|SOX10||Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease||AD||56||148|
|SUMF1||Multiple sulfatase deficiency||AR||21||53|
|TREX1||Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndrome||AD/AR||30||71|
|TTC19||Mitochondrial complex III deficiency, nuclear type 2||AR||13||10|
|TUBB4A*||Leukodystrophy, hypomyelinating, Dystonia||AD||39||42|
|ZFYVE26||Spastic paraplegia 15||AR||63||39|
* 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 Leukodystrophy and Leukoencephalopathy 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 suboptimal coverage in our assay are marked with number sign (#) and 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. Gene is considered to have suboptimal coverage when >90% of the gene's target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. 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 leukodystrophy and leukoencephalopathy panel covers classical genes associated with leukoencephalopathy and leukodystrophy. 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.