Leukodystrophy and Leukoencephalopathy Panel

  • Is a 81 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.

Analysis methods
  • PLUS

4 weeks

Number of genes


Test code


Panel size


CPT code *
* The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payer being billed.


The Blueprint Genetics Leukodystrophy and Leukoencephalopathy Panel (test code NE2001):

ICD codes

Commonly used ICD-10 code(s) when ordering the Leukodystrophy and Leukoencephalopathy Panel

ICD-10 Disease
E75.25 Leukodystrophy

Sample Requirements

  • 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

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCD1* Adrenoleukodystrophy XL 95 663
ADAR Dyschromatosis symmetrica hereditaria, Aicardi-Goutières syndrome AD/AR 25 226
AIFM1 Deafness, Combined oxidative phosphorylation deficiency 6, Cowchock syndrome XL 27 31
AIMP1 Leukodystrophy, hypomyelinating AR 4 5
ALDH3A2 Sjogren-Larsson syndrome AR 74 111
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
ARSA Metachromatic leukodystrophy AR 113 246
ASPA Aspartoacylase deficiency (Canavan disease) AR 54 102
CLCN2 Leukoencephalopathy with ataxia, Epilepsy AD/AR 30 36
COA7 Spinocerebellar ataxia, Charcot-Marie-Tooth disease AR 2 7
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
CYP27A1 Cerebrotendinous xanthomatosis AR 69 110
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
DEGS1# Leukodystrophy, hypomyelinating AR
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
EPRS Leukodystrophy, hypomyelinating AR 6 6
FA2H Spastic paraplegia AR 18 51
FAM126A Leukodystrophy, hypomyelinating AR 8 12
FDX1L Myopathy AR 1 2
FOLR1 Cerebral folate deficiency AR 10 28
FOXRED1 Leigh syndrome, Mitochondrial complex I deficiency AR 15 8
GALC Krabbe disease AR 107 243
GFAP Alexander disease AD 114 131
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
L2HGDH L-2-hydroxyglutaric aciduria AR 15 79
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
NKX6-2 Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy AR 4 8
NOTCH3 Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Lateral meningocele syndrome AD 87 364
NT5C2 Spastic paraplegia 45 AR 8 7
NUBPL Mitochondrial complex I deficiency AR 9 10
PLP1 Spastic paraplegia, Pelizaeus-Merzbacher disease XL 60 348
POLR3A Leukodystrophy, hypomyelinating AR 29 91
POLR3B Leukodystrophy, hypomyelinating AR 19 58
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
RNASEH2A Aicardi-Goutières syndrome AR 13 21
RNASEH2B Aicardi-Goutières syndrome AR 16 41
RNASEH2C Aicardi-Goutières syndrome AR 6 14
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
SLC1A4 Spastic tetraplegia, thin corpus callosum, and progressive microcephaly AR 4 8
SNORD118 Leukoencephalopathy, brain calcifications, and cysts (Labrune syndrome) AR 6 39
SOX10 Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease, Kallmann syndrome 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), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence 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
AIFM1 ChrX:129274636 c.697-44T>G NM_004208.3
ALDH3A2 Chr17:19561044 c.681-14T>A/G NM_001031806.1
ALDH3A2 Chr17:19561044 c.681-14T>A NM_001031806.1
ALDH3A2 Chr17:19561044 c.681-14T>G NM_001031806.1
ARSA Chr22:51064121 c.1108-12C>G NM_000487.5 rs757806374
ARSA Chr22:51064129 c.1108-20A>G NM_000487.5
COL4A1 Chr13:110802675 c.*35C>A NM_001845.4
COL4A1 Chr13:110802678 c.*32G>A/T NM_001845.4
COL4A1 Chr13:110802679 c.*31G>T NM_001845.4
CSF1R Chr5:149440654 c.1859-119G>A NM_005211.3
D2HGDH Chr2:242680425 c.293-23A>G NM_152783.3
DARS2 Chr1:173797449 c.228-22T>C NM_018122.4
DARS2 Chr1:173797449 c.228-22T>A NM_018122.4
DARS2 Chr1:173797450 c.228-21_228-20delTTinsC NM_018122.4
DARS2 Chr1:173797450 c.228-21_228-20delTTinsCC NM_018122.4
DARS2 Chr1:173797455 c.228-16C>A NM_018122.4
DARS2 Chr1:173797455 c.228-16C>G NM_018122.4
DARS2 Chr1:173797456 c.228-15C>G NM_018122.4
DARS2 Chr1:173797456 c.228-15C>A NM_018122.4
DARS2 Chr1:173797459 c.228-12C>A NM_018122.4
DARS2 Chr1:173797460 c.228-11C>G NM_018122.4
EIF2B5 Chr3:183855941 c.685-13C>G NM_003907.2
GALC Chr14:88401064 c.*12G>A NM_000153.3 rs372641636
GALC Chr14:88459574 c.-66G>C NM_000153.3 rs146439771
GALC Chr14:88459575 c.-67T>G NM_000153.3 rs571945132
GALC Chr14:88459917 c.-74T>A NM_001201402.1
GALC Chr14:88459971 c.-128C>T NM_001201402.1 rs181956126
GJC2 Chr1:228337558 c.-170A>G NM_020435.3
GJC2 Chr1:228337561 c.-167A>G NM_020435.3
GJC2 Chr1:228337709 c.-20+1G>C NM_020435.3
L2HGDH Chr14:50735527 c.906+354G>A NM_024884.2
MLC1 Chr22:50502853 c.895-226T>G NM_015166.3
MLC1 Chr22:50523373 c.-42C>T NM_015166.3 rs771159578
NDUFAF5 Chr20:13767051 c.223-907A>C NM_024120.4
NOTCH3 Chr19:15303132 c.341-26_341-24delAAC NM_000435.2
PLP1 ChrX:103031997 c.4+78_4+85delGGGGGTTC NM_000533.3
PLP1 ChrX:103041680 c.453+28_453+46delTAACAAGGGGTGGGGGAAA NM_000533.3
PLP1 ChrX:103042405 c.454-322G>A NM_000533.3
PLP1 ChrX:103042413 c.454-314T>A/G NM_000533.3
PLP1 ChrX:103042413 c.454-314T>A NM_000533.3
PLP1 ChrX:103042413 c.454-314T>G NM_000533.3
POLR3A Chr10:79737218 c.*18C>T NM_007055.3
POLR3A Chr10:79743781 c.3337-11T>C NM_007055.3
POLR3A Chr10:79769273 c.1909+22G>A NM_007055.3 rs191875469
POLR3A Chr10:79769277 c.1909+18G>A NM_007055.3 rs267608677
POLR3B Chr12:106804589 c.967-15A>G NM_018082.5
POLR3B Chr12:106831447 c.1857-12A>G NM_018082.5 rs528038639
PSAP Chr10:73583679 c.778-26C>A NM_001042465.1
RNASEH2B Chr13:51501530 c.65-13G>A NM_024570.3
RNASEH2B Chr13:51519550 c.511-13G>A NM_024570.3
SERAC1 Chr6:158576548 c.92-165C>T NM_032861.3
SERAC1 Chr6:158576622 c.92-239G>C NM_032861.3
SNORD118 Chr17:8076761 NR_033294.1 rs116395281
SNORD118 Chr17:8076761 NR_033294.1
SNORD118 Chr17:8076762 NR_033294.1 rs201787275
SOX10 Chr22:38379877 c.-84-2A>T NM_006941.3
SOX10 Chr22:38412215 c.-31954C>T NM_006941.3 rs606231342
SOX10 Chr22:38412781 c.-32520C>G NM_006941.3
TTC19 Chr17:15903121 c.-42G>T NM_017775.3 rs769078093

Added and removed genes from the panel

Genes added Genes removed

Test Strengths

The strengths of this test include:
  • CAP accredited laboratory
  • 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 publicly available analytic validation demonstrating complete details of test performance
  • ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see ‘Non-coding disease causing variants covered by this panel’ in the Panel Content section)
  • Our rigorous 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

The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: AP4S1 (NM_001254727:6), DEGS1 (NM_001321541:3). 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).

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 (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 genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sectioned from our high-quality, clinical grade NGS assay. Please see our sequencing and detection performance table for details regarding our ability to detect different types of alterations (Table).

Assays have been validated for various sample types including EDTA-blood, isolated DNA (excluding from formalin fixed paraffin embedded tissue), saliva and dry blood spots (filter cards). These sample types were selected in order to maximize the likelihood for high-quality DNA yield. The diagnostic yield varies depending on the assay used, referring healthcare professional, hospital and country. Plus analysis increases the likelihood of finding a genetic diagnosis for your patient, as large deletions and duplications cannot be detected using sequence analysis alone. Blueprint Genetics’ Plus Analysis is a combination of both sequencing and deletion/duplication (copy number variant (CNV)) analysis.

Performance of Blueprint Genetics high-quality, clinical grade NGS sequencing assay for panels.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.89% (99,153/99,266) >99.9999%
Insertions, deletions and indels by sequence analysis
1-10 bps 99.2% (7,745/7,806) >99.9999%
11-50 bps 99.13% (2,524/2,546) >99.9999%
Copy number variants (exon level dels/dups)
1 exon level deletion (heterozygous) 100% (20/20) NA
1 exon level deletion (homozygous) 100% (5/5) NA
1 exon level deletion (het or homo) 100% (25/25) NA
2-7 exon level deletion (het or homo) 100% (44/44) NA
1-9 exon level duplication (het or homo) 75% (6/8) NA
Simulated CNV detection
5 exons level deletion/duplication 98.7% 100.00%
Size range (0.1-47 Mb) 100% (25/25)
The performance presented above reached by Blueprint Genetics high-quality, clinical grade NGS sequencing assay with the following coverage metrics
Mean sequencing depth 143X
Nucleotides with >20x sequencing coverage (%) 99.86%


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 and regulatory 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 including, 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, ordering providers have access to the details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with <20X sequencing depth if applicable. This reflects our mission to build fully transparent diagnostics where ordering providers can easily visualize the 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 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 heterozygous and homo/hemizygous copy number variations with a size <10 and <3 target exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen and confirmed 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, abstracts and variant databases used to help ordering providers 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. We do not recommend using variants of uncertain significance (VUS) for family member risk stratification or patient management. Genetic counseling is recommended.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Our internal database and our understanding of variants and related phenotypes increases with every case analyzed. 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.

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