Leukodystrophy and Leukoencephalopathy Panel

SEQmethod-seq-icon Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 21 days. DEL/DUPmethod-dup-icon Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 21 days. PLUSmethod-plus-icon Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 21 days.

Test code: NE2001

The Blueprint Genetics Leukodystrophy and Leukoencephalopathy Panel is a 42 gene test for genetic diagnostics of patients with clinical suspicion of leukodystrophy or leukoencephalopathy.

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 in even the same family. Genetic testing is leading to 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 of a specific hereditary disease. This panel is part of Comprehensive Epilepsy Panel.

About Leukodystrophy and Leukoencephalopathy

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 a disorder that is heritable and result in white matter abnormalities but do not necessarily meet strict criteria of a leukodystrophy (PubMed: 25649058). As an example, hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a neurodegenerative disease clinically characterized by slowly progressive cognitive decline and motor dysfunction. Neuropathology shows diffuse degeneration in the white matter, with prominent presence of widespread axonal spheroids. The affected patients of a family sharing the same CSF1 mutation may have varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology (PubMed: 26141825).


Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more.

Genes in the Leukodystrophy and Leukoencephalopathy Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ADARDyschromatosis symmetrica hereditaria, Aicardi-Goutières syndromeAD/AR16202
AIMP1Leukodystrophy, hypomyelinatingAR35
ARSAMetachromatic leukodystrophyAR61212
ASPAAspartoacylase deficiency (Canavan disease)AR1990
CLCN2Leukoencephalopathy with ataxia, EpilepsyAD/AR1829
COL4A1Schizencephaly, Anterior segment dysgenesis with cerebral involvement, Retinal artery tortuosity, Porencephaly, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, Brain small vessel diseaseAD2788
COX15Leigh syndrome, Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiencyAR65
CSF1RLeukoencephalopathy, diffuse hereditary, with spheroidsAD4470
DARS2Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevationAR1556
EARS2Combined oxidative phosphorylation deficiencyAR826
EIF2B1Leukoencephalopathy with vanishing white matter, OvarioleukodystrophyAR79
EIF2B2Leukoencephalopathy with vanishing white matter, OvarioleukodystrophyAR825
EIF2B3Leukoencephalopathy with vanishing white matter, OvarioleukodystrophyAR520
EIF2B4Leukoencephalopathy with vanishing white matter, OvarioleukodystrophyAR629
EIF2B5Leukoencephalopathy with vanishing white matter, OvarioleukodystrophyAR1495
FAM126ALeukodystrophy, hypomyelinatingAR612
FOLR1Cerebral folate deficiencyAR424
FOXRED1Leigh syndrome, Mitochondrial complex I deficiencyAR107
GALCKrabbe diseaseAR35210
GFAPAlexander diseaseAD110112
GJC2Spastic paraplegia, Lymphedema, hereditary, Leukodystrophy, hypomyelinatingAD/AR1553
HEPACAMMegalencephalic leukoencephalopathy with subcortical cysts, remittingAD/AR923
HSPD1*Spastic paraplegia, Leukodystrophy, hypomyelinatingAD/AR44
L2HGDHL-2-hydroxyglutaric aciduriaAR875
MARS2Combined oxidative phosphorylation deficiencyAR65
MLC1Megalencephalic leukoencephalopathy with subcortical cystsAR17111
NDUFAF5Mitochondrial complex I deficiencyAR810
NOTCH3Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)AD22313
PLP1Spastic paraplegia, Pelizaeus-Merzbacher diseaseXL41266
POLR3ALeukodystrophy, hypomyelinatingAR2167
POLR3BLeukodystrophy, hypomyelinatingAR1154
PSAPKrabbe disease, atypical, Metachromatic leukodystrophy due to saposin-b deficiency, Combined saposin deficiency, Gaucher disease, atypical, due to saposin C deficiencyAR1524
RNASEH2AAicardi-Goutières syndromeAR1221
RNASEH2BAicardi-Goutières syndromeAR539
RNASEH2CAicardi-Goutières syndromeAR414
RNASET2Leukoencephalopathy, cystic, without megalencephalyAR611
SAMHD1Aicardi-Goutières syndromeAR2248
SOX10Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung diseaseAD31119
SUMF1Multiple sulfatase deficiencyAR1851
TREX1Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndromeAD/AR2465
TUBB4A*Leukodystrophy, hypomyelinating, DystoniaAD3536
  • * Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Blueprint Genetics offers a comprehensive Leukodystrophy and Leukoencephalopathy Panel that covers classical genes associated with leukodystrophy and leukoencephalopathy. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

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. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes


ICD codes

Commonly used ICD-10 codes when ordering the Leukodystrophy and Leukoencephalopathy Panel


Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • 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.

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