Epileptic Encephalopathy Panel

Last modified: Jun 12, 2018

Summary

  • Is a 128 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion of epileptic encephalopathy. The genes on this panel are included on the Comprehensive Epilepsy Panel.

Analysis methods

  • PLUS
  • SEQ
  • DEL/DUP

Availability

4 weeks

Number of genes

128

Test code

NE0401

Panel size

Large

CPT codes

SEQ 81302
SEQ 81405
SEQ 81406
DEL/DUP 81479

Summary

The Blueprint Genetics Epileptic Encephalopathy Panel (test code NE0401):

  • Is a 128 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • 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.

Epileptic encephalopathies are characterized by epileptiform abnormalities associated with progressive cerebral dysfunction. They typically present at an early age and manifest with EEG paroxysmal activity that is often aggressive, seizures that are commonly multi-form and intractable, cognitive, behavioural and neurological deficits that may be relentless and sometimes early death. Cognitive deficits and behavioural disturbances are presumed to be the main, and sometimes the first and only unique, manifestation of electrographic epileptic discharges in epileptic encephalopathies. In the classification of the International League Against Epilepsy, eight age-related epileptic encephalopathy syndromes are recognized. These syndromes include early myoclonic encephalopathy and Ohtahara syndrome (also known as early infantile epileptic encephalopathy with suppression-bursts) in the neonatal period, West syndrome (also known as infantile spasms) and Dravet syndrome in infancy, myoclonic status in nonprogressive encephalopathies, and Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and epilepsy with continuous spike waves during slow wave sleep in childhood and adolescences. Other epileptic syndromes such as migrating partial seizures in infancy and severe epilepsy with multiple independent spike foci may be reasonably added. A common feature is that these disorders are usually refractory to standard antiepileptic drugs (AEDs). The aetiology of the epileptic encephalopathies is variable and includes malformations, metabolic disease and genetic conditions. Genetic testing is very useful in the differential diagnosis of hereditary epileptic encephalopathies. Prenatal diagnosis is possible in families with a known genetic etiology. Depending of the specific syndrome and causative gene, epileptic encephalopathy can be inherited in an autosomal recessive, autosomal dominant or X-linked manner. Often, mutations occur de novo.

Genes in the Epileptic Encephalopathy Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABAT GABA-transaminase deficiency AR 11 12
ADAR Dyschromatosis symmetrica hereditaria, Aicardi-Goutières syndrome AD/AR 24 211
ADSL Adenylosuccinase deficiency AR 24 56
ALDH7A1 Epilepsy, pyridoxine-dependent AR 50 113
ALG13 Congenital disorder of glycosylation XL 5 9
AMT Glycine encephalopathy AR 25 95
APOPT1 Mitochondrial complex IV deficiency AR 4 5
ARHGEF9 Epileptic encephalopathy, early infantile XL 7 21
ARX Lissencephaly, Epileptic encephalopathy, Corpus callosum, agenesis of, with abnormal genitalia, Partington syndrome, Proud syndrome, Hydranencephaly with abnormal genitalia, Mental retardation XL 66 89
ASNS* Asparagine synthetase deficiency AR 18 15
BRAT1 Rigidity and multifocal seizure syndrome, lethal neonatal AR 17 17
CACNA1A Migraine, familial hemiplegic, Episodic ataxia, Spinocerebellar ataxia 6, Epileptic encephalopathy, early infantile, 42 AD 121 211
CASK Mental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardation XL 80 104
CDKL5 Epileptic encephalopathy, early infantile, Rett syndrome, atypical, Angelman-like syndrome XL 291 313
CHD2 Epileptic encephalopathy, childhood-onset AD 70 48
CLCN4 Mental retardation, X-linked 49 XL 21 9
CNTNAP2 Pitt-Hopkins like syndrome, Cortical dysplasia-focal epilepsy syndrome AR 42 69
COX6B1 Mitochondrial complex IV deficiency AR 2 3
CPT2 Carnitine palmitoyltransferase II deficiency AR 48 107
D2HGDH D-2-hydroxyglutaric aciduria 1 AR 10 32
DCX Lissencephaly, Subcortical laminal heterotopia XL 131 142
DNM1* Epileptic encephalopathy, early infantile AD 26 21
DNM1L Encephalopathy due to defective mitochondrial and peroxisomal fission 1 AD 18 20
DOCK7 Epilepitic encephalopathy AR 17 4
ECHS1 Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency AR 23 31
EEF1A2 Epileptic encephalopathy, early infantile, Mental retardation AD 12 11
ETHE1 Ethylmalonic encephalopathy AR 36 35
FAR1* Peroxisomal fatty acyl-CoA reductase 1 disorder AR 4 4
FARS2 Combined oxidative phosphorylation deficiency 14, Spastic paraplegia 77, autosomal recessive AR 19 18
FGF12 Epileptic encephalopathy, early infantile, 47 AD 6 9
FLNA Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects XL 119 235
FOXG1 Rett syndrome, congenital variant AD 99 146
GABRA1 Epileptic encephalopathy, early infantile, Epilepsy, childhood absence, Epilepsy, juvenile myoclonic AD 23 32
GABRB2 Epileptic encephalopathy AD 19 14
GABRB3 Epilepsy, childhood absence AD 18 41
GABRG2 Generalized epilepsy with febrile seizures plus, Familial febrile seizures, Dravet syndrome, Epilepsy, childhood absence AD 32 32
GAMT Guanidinoacetate methyltransferase deficiency AR 18 58
GLDC Glycine encephalopathy AR 105 424
GNAO1 Epileptic encephalopathy, early infantile, Epileptic encephalopathy, early infantile, 17 AD 25 27
GPHN Hyperekplexia, Molybdenum cofactor deficiency AD/AR 29 20
GRIN1 Mental retardation, autosomal dominant 8 AD 35 27
GRIN2A Epilepsy, focal, with speech disorder AD 52 83
GRIN2B Epileptic encephalopathy, early infantile, Mental retardation AD 64 64
GTPBP3 Combined oxidative phosphorylation deficiency 23 AR 14 15
HCN1 Epileptic encephalopathy, early infantile AD 11 11
HECW2 Neurodevelopmental disorder with hypotonia, seizures, and absent language AD 9 4
HEPACAM Megalencephalic leukoencephalopathy with subcortical cysts, remitting AD/AR 12 26
HIBCH 3-hydroxyisobutryl-CoA hydrolase deficiency AR 19 13
HNRNPU Intellectual disability and seizures AD 29 66
HTT Huntington disease AD/AR 8 7
KCNA2 Epileptic encephalopathy, early infantile AD 13 15
KCNB1 Early infantile epileptic encephalopathy AD 22 29
KCNQ2 Epileptic encephalopathy, early infantile, Benign familial neonatal seizures, Myokymia AD 324 245
KCNQ3 Seizures, benign neonatal AD 18 17
KCNT1 Epilepsy, nocturnal frontal lobe AD 33 37
KIF1A Spastic paraplegia, Neuropathy, hereditary sensory, Mental retardation AD/AR 58 39
LRPPRC Leigh syndrome, French-Canadian type AR 20 15
LYRM7# Mitochondrial complex III deficiency, nuclear type 8 AR 5 7
MBD5 Mental retardation AD 48 87
MECP2 Angelman-like syndrome, Autism, Rett syndrome, Encephalopathy, Mental retardation XL 471 984
MEF2C Mental retardation AD 39 74
MOCS1* Molybdenum cofactor deficiency AR 7 35
MRPL44 Combined oxidative phosphorylation deficiency 16 AR 2 2
MTFMT Combined oxidative phosphorylation deficiency 15 AR 15 16
MTHFR Homocystinuria due to MTHFR deficiency AR 63 120
NACC1 Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM) AD 2 2
NDUFAF6 Mitochondrial complex I deficiency, Leigh syndrome AR 18 8
NDUFS2 Mitochondrial complex I deficiency AR 5 22
NDUFS4 Mitochondrial complex I deficiency, Leigh syndrome AR 10 17
NDUFS7 Mitochondrial complex I deficiency, Leigh syndrome AR 5 7
NDUFS8 Mitochondrial complex I deficiency, Leigh syndrome AR 13 12
NDUFV1 Mitochondrial complex I deficiency AR 19 34
NECAP1* Epileptic encephalopathy, early infantile AR 1 1
NRXN1 Pitt-Hopkins like syndrome, Epilepsy, hearing loss, and mental retardation syndrome; EHLMRS AD/AR 81 306
NUBPL Mitochondrial complex I deficiency AR 10 9
PCDH19 Epileptic encephalopathy, early infantile XL 104 160
PIGA* Multiple congenital anomalies-hypotonia-seizures syndrome XL 24 24
PLCB1 Epileptic encephalopathy, early infantile AR 7 10
PNKP Epileptic encephalopathy, early infantile, Ataxia-oculomotor AR 34 17
PNPO Pyridoxamine 5'-phosphate oxidase deficiency AR 15 30
POLG POLG-related ataxia neuropathy spectrum disorders, Sensory ataxia, dysarthria, and ophthalmoparesis, Alpers syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome AD/AR 90 280
PURA Mental retardation AD 66 42
RMND1* Combined oxidative phosphorylation deficiency AR 18 15
RNASEH2A Aicardi-Goutières syndrome AR 13 21
RNASEH2B Aicardi-Goutières syndrome AR 13 40
ROGDI Kohlschutter-Tonz syndrome AR 11 13
SAMHD1 Aicardi-Goutières syndrome, Chilblain lupus 2 AR 23 55
SCN1A Migraine, familial hemiplegic, Epileptic encephalopathy, early infantile, Generalized epilepsy with febrile seizures plus, Early infantile epileptic encephalopathy 6, Generalized epilepsy with febrile seizures plus, type 2 , Febrile seizures, familial 3A AD 654 1489
SCN1B Atrial fibrillation, Brugada syndrome, Generalized epilepsy with febrile seizures plus, Epilepsy, generalized, with febrile seizures plus, type 1, Epileptic encephalopathy, early infantile, 52 AD 15 29
SCN2A Epileptic encephalopathy, early infantile, Seizures, benign familial infantile AD 173 226
SCN8A Cognitive impairment, Epileptic encephalopathy, early infantile AD 92 83
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 23 48
SIK1 Epileptic encephalopathy, early infantile AD 5 6
SLC2A1 Stomatin-deficient cryohydrocytosis with neurologic defects, Epilepsy, idiopathic generalized, GLUT1 deficiency syndrome AD/AR 98 262
SLC6A8* Creatine deficiency syndrome XL 32 128
SLC9A6 Mental retardation, syndromic, Christianson XL 24 21
SLC12A5 Epileptic encephalopathy, early infantile AR 4 14
SLC13A5 Epileptic encephalopathy, early infantile AR 16 19
SLC19A3 Thiamine metabolism dysfunction syndrome AR 25 37
SLC25A1 Combined D-2- and L-2-hydroxyglutaric aciduria AR 8 16
SLC25A22 Epileptic encephalopathy, early infantile AR 7 10
SLC35A2 Congenital disorder of glycosylation XL 15 15
SNAP25 Myasthenic syndrome, congenital AD 2 3
SPTAN1 Epileptic encephalopathy, early infantile AD 12 36
ST3GAL3 Epileptic encephalopathy, early infantile, Mental retardation AR 3 3
ST3GAL5 Ganglioside GM3 synthase deficiency AR 7 5
STXBP1 Epileptic encephalopathy, early infantile AD 129 176
SYN1 Epilepsy, with variable learning disabilities and behavior disorders XL 11 7
SYNGAP1 Mental retardation AD 82 69
SYNJ1 Epileptic encephalopathy, early infantile, 53, Parkinson disease 20, early-onset AR 8 23
SZT2 Epileptic encephalopathy, early infantile AR 9 19
TBC1D24 Deafness, Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome, Deafness, autosomal dominant, 65, Myoclonic epilepsy, infantile, familial, Epileptic encephalopathy, early infantile, 16 AD/AR 41 51
TBCD Early-onset progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT) AR 17 21
TBCE Progressive encephalopathy with amyotrophy and optic atrophy (PEAMO) AR 11 7
TBCK Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 AR 13 14
TCF4 Corneal dystrophy, Fuchs endothelial, Pitt-Hopkins syndrome AD 86 141
TREX1 Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndrome AD/AR 30 68
TSC1 Lymphangioleiomyomatosis, Tuberous sclerosis AD 138 346
TSC2 Lymphangioleiomyomatosis, Tuberous sclerosis AD 322 1137
TTC19 Mitochondrial complex III deficiency, nuclear type 2 AR 13 9
UBA5* Epileptic encephalopathy, early infantile, 44, Spinocerebellar ataxia, autosomal recessive 24 AR 16 14
UBE3A* Angelman syndrome AD 165 193
UNC80 Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 AR 24 16
WDR45 Neurodegeneration with brain iron accumulation XL 37 70
WWOX Epileptic encephalopathy, early infantile, Spinocerebellar ataxia AR 38 42
ZEB2* Mowat-Wilson syndrome AD 135 280

* 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 the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ADSL Chr22:40742514 c.-49T>C NM_000026.2
ALDH7A1 Chr5:125907053 c.696-502G>C NM_001182.4
AMT Chr3:49459938 c.-55C>T NM_000481.3 rs386833677
CACNA1A Chr19:13341036 c.5404-13G>A NM_001127221.1
CDKL5 ChrX:18525053 c.-162-2A>G NM_003159.2 rs786204973
D2HGDH Chr2:242680425 c.293-23A>G NM_152783.3
FGF12 Chr3:191857076 c.*4722T>C NM_021032.4
GABRA1 Chr5:161274418 c.-248+1G>T NM_000806.5
GABRB3 Chr15:27020313 c.-2204G>A NM_000814.5
GABRB3 Chr15:27020399 c.-2290T>C NM_000814.5 rs546389769
GAMT Chr19:1399508 c.391+15G>T NM_138924.2 rs367567416
MOCS1 Chr6:39874534 c.*365_*366delAG NM_005943.5 rs397518419
MTHFR Chr1:11863212 c.-13-28_-13-27delCT NM_005957.4 rs786204005
MTHFR Chr1:11850973 c.1753-18G>A NM_005957.4 rs777661576
NDUFAF6 Chr8:96046914 c.298-768T>C NM_152416.3 rs575462405
NDUFS7 Chr19:1386643 c.17-1167C>G NM_024407.4
NUBPL Chr14:32319298 c.815-27T>C NM_025152.2 rs118161496
PNKP Chr19:50364799 c.1387-33_1386+49delCCTCCTCCCCTGACCCC NM_007254.3 rs752902474
RNASEH2B Chr13:51501530 c.65-13G>A NM_024570.3
SCN1A Chr2:166913031 c.384-21T>A NM_006920.4 rs373168416
SCN1A Chr2:166854699 c.4306-14T>G NM_006920.4
SCN1A Chr2:166848946 c.4820-14T>G NM_006920.4
SCN1A Chr2:166908215 c.964+14T>G NM_006920.4 rs794726837
SLC19A3 Chr2:228560811 c.980-14A>G NM_025243.3 rs200542114
SLC2A1 Chr1:43395462 c.680-11G>A NM_006516.2
TBCD Chr17:80851411 c.1564-12C>G NM_005993.4
TSC2 Chr16:2098067 c.-30+1G>C NM_000548.3 rs587778004
TSC2 Chr16:2127477 c.2838-122G>A NM_000548.3
TSC2 Chr16:2138031 c.5069-18A>G NM_000548.3 rs45484794
TSC2 Chr16:2110656 c.976-15G>A NM_000548.3 rs45517150
ZEB2 Chr2:145274987 c.-69-1G>A NM_014795.3

Test strength

The strengths of this test include:
  • 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

Test limitations

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 Blueprint Genetics epileptic encephalopathy panel covers classical genes associated with epileptic encephalopathy. 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%

Bioinformatics

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.

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 of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for 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.

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.