NCL and Progressive Myoclonic Epilepsy 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: NE1901

The Blueprint Genetics NCL and Progressive Myoclonic Epilepsy Panel is a 28 gene test for genetic diagnostics of patients with clinical suspicion of neuronal ceroid lipofuscinosis or progressive myoclonic epilepy.

The panel covers genes for several entities including but not restricted to neuronal ceroid lipofuscinoses (NCL), Lafora disease, Unverricht-Lundborg disease and sialidoses. Most progressive myoclonic epilepsies (PMEs), but not all, are monogenic, autosomal recessive inherited diseases, and most diseases genes, but not all, encode lysosomal proteins. This panel is part of The Comprehensive Epilepsy Panel.

About NCL and Progressive Myoclonic Epilepsy

The progressive myoclonic epilepsies (PME) are a group of rare inherited disorders characterized by seizures, myoclonus, and progressive neurological degeneration. Patients may also exhibit cerebellar ataxia, dementia, neuropathy, and myopathy. It encompasses different diagnostic entities and the common forms include neuronal ceroid lipofuscinoses (NCLs), Unverricht-Lundborg disease and Lafora disease among other more rare forms of PMEs. Recently, a recurrent de novo mutation in KCNC1 was identified as a new major cause for PME (PubMed 25401298). NCLs are the largest group of PME. The overall prevalence of NCL is reported to be approximately 1.5-9 per million. In the pregenetic era, cinical phenotypes of NCL have been characterized according to three main features: age-of-onset, the order of presentation of the three main symptoms (myoclonus and seizures, cognitive and motor decline, and retinal pathology and visual loss), and electron microscopic (EM) findings. There is genetic and allelic heterogeneity. The majority of NCLs are inherited in an autosomal recessive manner. CLN4 is the only autosomal dominant NCL. Pathogenic variants in thirteen genes (PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, KCTD7) are known to cause NCL. Unverricht-Lundborg disease (ULD) starts usually in childhood but improves in adulthood when myoclonus lessens in intensity, seizures tend to stop or are readily controllable. ULD is inherited in autosomal recessive manner and is due to mutations in CSTB. The Panel does not detect the expansion of a 12-nucleotide repeat (rs193922905) in the promoter region of CSTB. ULD patients who do not have the dodecamer repeat expansion on one of their alleles have other damaging, but not wholly inactivating mutations. Lafora disease is characterized by myoclonus and generalized tonic-clonic seizures, visual hallucinations, and progressive neurologic degeneration leading to death in 4-10 years after the onset. Lafora disease is inherited in an autosomal recessive manner and is caused by mutations in EPM2A or NHLRC1. The diagnostic yield of these genes is reported to be 84-97%. Prevalence of both ULD and Lafora disease varies significantly between countries.

Availability

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 NCL and Progressive Myoclonic Epilepsy Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
AFG3L2*Spastic ataxia, Spinocerebellar ataxiaAD/AR1925
ASAH1Spinal muscular atrophy with progressive myoclonic epilepsy, Farber lipogranulomatosisAR1153
ATP13A2Parkinson disease (Kufor-Rakeb syndrome)AR1135
CERS1Epilepsy, progressive myoclonicAR41
CLN3Ceroid lipofuscinosis, neuronalAR6964
CLN5Ceroid lipofuscinosis, neuronalAR4042
CLN6Ceroid lipofuscinosis, neuronalAR2180
CLN8Ceroid lipofuscinosis, neuronalAR3135
CSTBEpilepsy, progressive myoclonicAR1613
CTSDCeroid lipofuscinosis, neuronalAR1115
CTSFNeuronal ceroid lipofuscinosisAR79
DNAJC5Kufs disease,, Ceroid lipofuscinosis, neuronal 4, ParryAD22
EPM2AEpilepsy, progressive myoclonicAR1274
FOLR1Cerebral folate deficiencyAR424
GOSR2*Epilepsy, progessive myoclonicAR53
GRNFrontotemporal lobar degeneration with TDP43 inclusions, GRN-related, Neuronal ceroid lipofuscinosisAD/AR24165
KCNC1Epilepsy, progressive myoclonicAD11
KCTD7*Epilepsy, progressive myoclonicAR1213
MFSD8Ceroid lipofuscinosis, neuronalAR1941
NEU1SialidosisAR1956
NHLRC1Epilepsy, progressive myoclonicAR1470
PPT1Ceroid lipofuscinosis, neuronalAR7277
PRICKLE1Epilepsy, progressive myoclonicAD/AR414
PRICKLE2Epilepsy, progessive myoclonicAD16
SCARB2Epilepsy, progressive myoclonicAR2222
SERPINI1Encephalopathy, familial, with neuroserpin inclusion bodiesAD57
TBC1D24Deafness, Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndromeAD/AR2741
TPP1Ceroid lipofuscinosis, neuronal, Spinocerebellar ataxiaAR33109
  • * 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 NCL and progressive myoclonic epilepsy panel that covers classical genes associated with action myoclonus-renal failure syndrome, neuronal ceroid lipofuscinosis, North Sea progressive myoclunus epilepsy, progressive myoclonic epilepy, sialidoses type I and II and spinal-muscular atrophy-progressive myoclonic epilepsy. 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.

Please see our latest validation report showing sensitivity and specificity for SNPs and indels, sequencing depth, % of the nucleotides reached at least 15x coverage etc. If the Panel is not present in the report, data will be published when the Panel becomes available for ordering. 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. All the Panels available for ordering have sensitivity and specificity higher than > 0.99 to detect single nucleotide polymorphisms and a high sensitivity for indels ranging 1-19 bp. 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. Detection limit for Del/Dup analysis varies through the genome from one to six exon Del/Dups depending on exon size, sequencing coverage and sequence content.

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

SEQ81479
DEL/DUP81479


ICD codes

Commonly used ICD-10 codes when ordering the NCL and Progressive Myoclonic Epilepsy Panel

ICD-10Disease
E75.4Neuronal ceroid lipofuscinosis

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.