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Early Infantile Epileptic Encephalopathy Sequencing Panel

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

NGS Sequencing

Test Code Test Copy GenesCPT Code Copy CPT Codes
1961 ACY1 81479 Add to Order
ADSL 81479
ALDH7A1 81406
ARFGEF2 81479
ARHGEF9 81479
ARX 81404
BCKDK 81479
CDKL5 81406
CHD2 81479
CHRNA2 81479
CHRNA4 81405
CHRNB2 81405
CLN3 81479
CLN5 81479
CLN6 81479
CLN8 81479
CNTNAP2 81406
CSTB 81404
CTSD 81479
CTSF 81479
DEPDC5 81479
EPM2A 81404
FARS2 81479
FOLR1 81479
FOXG1 81404
GABRA1 81479
GABRB3 81479
GABRG2 81405
GAMT 81479
GNAO1 81479
GOSR2 81479
GRIN2A 81479
HCN1 81479
KCNA2 81479
KCNB1 81479
KCNJ10 81404
KCNQ2 81406
KCNQ3 81479
KCNT1 81479
KCTD7 81479
LGI1 81479
MBD5 81479
MECP2 81302
MEF2C 81479
MFSD8 81479
NHLRC1 81403
NPRL2 81479
NRXN1 81479
PCDH19 81405
PIGO 81479
PLCB1 81479
PNKP 81479
PNPO 81479
POLG 81406
PPT1 81479
PRRT2 81479
RELN 81479
ROGDI 81479
SCARB2 81479
SCN1A 81407
SCN1B 81404
SCN2A 81479
SCN8A 81479
SCN9A 81479
SLC13A5 81479
SLC19A3 81479
SLC25A22 81479
SLC2A1 81405
SLC35A2 81479
SLC9A6 81406
SPTAN1 81479
ST3GAL3 81479
ST3GAL5 81479
STX1B 81479
STXBP1 81406
SZT2 81479
TBC1D24 81479
TNK2 81479
TPP1 81479
TSC1 81406
TSC2 81407
WWOX 81479
Full Panel Price* $790.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
1961 Genes x (82) $790.00 81302, 81403, 81404(x6), 81405(x5), 81406(x8), 81407(x2), 81479(x59) Add to Order
Pricing Comment

We are happy to accommodate requests for single genes or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered on our PGxome Custom Panel.

Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

This panel includes genes causative for autosomal dominant, autosomal recessive and X-linked early infantile epileptic encephalopathy (EIEE). Extrapolating from previously published studies of next generation sequencing in large cohorts of patients with EIEE, we predict that our EIEE Panel will identify pathogenic variants more than 37% of EIEE cases with unknown cause (Lemke et al. 2012. PubMed ID: 22612257; Kodera et al. 2013. PubMed ID: 23662938; Carvill et al. 2013. PubMed ID: 23708187; Della Mina et al. 2015. PubMed ID: 24848745; Wang et al. 2014. PubMed ID:24818677; Ream et al. 2014. PubMed ID:25108116). In particular, clinical sensitivity for Autosomal Dominant Nocturnal Frontal Lobe Epilepsy is more than 25-35% while for autosomal dominant focal epilepsy, the sensitivity is more than 12-37% (Dibbens et al. 2013. PubMed ID:23542697; Ishida et al. 2013. PubMed ID:23542701; Picard et al. 2014. PubMed ID:24814846). This panel identifies pathogenic variants in 70-80% of Dravet syndrome patients (Ottman et al 2010. PubMed ID:20100225; Carvill et al 2014. PubMed ID:24623842; Gaily et al 2013. PubMed ID:23808377).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 ACY1$990.00 81479 Add to Order
ADSL$990.00 81479
ALDH7A1$990.00 81479
ARFGEF2$990.00 81479
ARHGEF9$990.00 81479
ARX$990.00 81403
BCKDK$990.00 81479
CDKL5$990.00 81405
CHD2$990.00 81479
CLN3$990.00 81479
CLN5$990.00 81479
CLN6$990.00 81479
CLN8$990.00 81479
CNTNAP2$990.00 81479
CSTB$990.00 81479
CTSD$990.00 81479
CTSF$990.00 81479
EPM2A$990.00 81479
FARS2$990.00 81479
FOLR1$990.00 81479
FOXG1$990.00 81479
GABRA1$990.00 81479
GABRB3$990.00 81479
GABRG2$990.00 81479
GAMT$990.00 81479
GNAO1$990.00 81479
GOSR2$990.00 81479
GRIN2A$990.00 81479
KCNJ10$990.00 81479
KCNQ2$990.00 81479
KCNQ3$990.00 81479
KCNT1$990.00 81479
KCTD7$990.00 81479
LGI1$990.00 81479
MBD5$990.00 81479
MECP2$990.00 81304
MEF2C$990.00 81479
MFSD8$990.00 81479
NHLRC1$990.00 81479
NRXN1$990.00 81479
PCDH19$990.00 81479
PLCB1$990.00 81479
PNKP$990.00 81479
PNPO$990.00 81479
POLG$990.00 81479
PPT1$990.00 81479
RELN$990.00 81479
ROGDI$990.00 81479
SCARB2$990.00 81479
SCN1A$990.00 81479
SCN1B$990.00 81479
SCN2A$990.00 81479
SCN8A$990.00 81479
SCN9A$990.00 81479
SLC19A3$990.00 81479
SLC25A22$990.00 81479
SLC2A1$990.00 81479
SLC9A6$990.00 81479
SPTAN1$990.00 81479
ST3GAL3$990.00 81479
ST3GAL5$990.00 81479
STXBP1$990.00 81479
SZT2$990.00 81479
TBC1D24$990.00 81479
TNK2$990.00 81479
TPP1$990.00 81479
TSC1$990.00 81405
TSC2$990.00 81406
Full Panel Price* $1490.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
600 Genes x (68) $1490.00 81304, 81403, 81405(x2), 81406, 81479(x63) Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$990

2-5

$1190

6-10

$1290

11-100

$1490

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

Large deletions or duplications that may not be detectable by sequencing have been reported in ARHGEF9, ARX, CDKL5, CHD2, FOXG1, GABRA1, GABRB3, GABRG2, GRIN2A, LGI1, MBD5, MECP2, MEF2C, PCDH19, PRRT2, SCN1A, SCN2A, SCN8A, SLC2A1, SLC9A6, SPTAN1, STX1B, STXBP1, TSC1 and TSC2 (Human Gene Mutation Database). Patients with an identifiable TSC pathogenic variant will have either a large deletion or duplication in up to 6% and 1% of cases in the TSC2 and TSC1 genes, respectively (Northrup et al. 2015. PubMed ID:20301399).

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Clinical Features

Early Infantile Epileptic Encephalopathy (EIEE) is a clinically and genetically heterogeneous neurodevelopmental disorder. The key feature of EIEE is onset of frequent and/or severe seizures within the first few weeks of life (Noh et al. 2012. PubMed ID: 22342633). These seizures are often associated with febrile events and may be refractory to treatment with anti-epileptic drugs (AEDs). EIEE patients may also present with an abnormal EEG pattern, such as the characteristic burst-suppression pattern seen in Ohtahara syndrome (Khan and Al Baradie 2012. PubMed ID: 23213494). Intellectual disability and psychomotor delay are common features of many severe epileptic encephalopathies.

Genetics

The most common causes of EIEE in infants are structural brain abnormalities and inborn errors of metabolism (Sharma and Prasad 2013. PubMed ID: 23250121, Wilmshurst et al. 2015. PubMed ID: 26122601). However, in cases of EIEE in which structural or metabolic defects are lacking, genetic factors are being found to play an increasing role. EIEE is a genetically heterogeneous disorder; over 100 genes have been suggested to be involved in disease pathogenesis (Lemke et al. 2012. PubMed ID: 22612257). Many EIEE cases are sporadic, occurring in families with no prior history of seizure (Allen et al. 2013. PubMed ID: 23934111). Sporadic cases of EIEE are commonly caused by dominant, de novo pathogenic variants in neuronally expressed genes. EIEE can also be inherited in an autosomal recessive manner. In this panel, we sequence a total of 82 genes. This panel covers 22 genes which are related to epilepsy treatment including ALDH7A1, BCKDK, CHRNA4, DEPDC5, FOLR1, GAMT,GRIN2A, KCNQ2, KCNQ3, KCNT1, PCDH19, PNPO, POLG, PRRT2, SCN1A, SCN2A, SCN8A, SLC19A3, SLC2A1, STXBP1, TSC1 and TSC2 (see the table below).

41 genes in which dominant or X-linked pathogenic variants have been reported in the literature to be causative for EIEE. Several of these genes are involved in well-characterized syndromes in which seizures are a predominant feature (Ottman et al. 2010. PubMed ID: 20100225; Wilmshurst et al. 2015. PubMed ID: 26122601) such as:

Tuberous Sclerosis: TSC1 and TSC2

Infantile Spasm: ADSL, ARX, CDKL5, PNPO, MEF2C, SCN1A, SCN2A, STXBP1, TSC1, TSC2

Focal epilepsy: CHRNA4, CHRNB2, CHRNA2, CNTNAP2, DEPDC5, KCNT1, GRIN2A, LGI1, NPRL2, PCDH19, RELN, SCN1A, TBC1D24

Dravet Syndrome: SCN1A, SCN1B, GABRG2, SCN2A, SCN9A, PCDH19, GABRA1, STXBP1 and CHD2.

Ohtahara Syndrome: ARX, STXBP1, SCN2A, KCNQ2, KCNT1, SLC25A22, CDKL5, PNKP and SPTAN1.

Generalized (or genetic) Epilepsy with Febrile Seizures Plus (GEFS+): SCN1A, SCN1B, SCN2A, SCN9A), GABRG2, STX1B

DEPDC5-related epilepsy

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy: CHRNA4, CHRNB2, CHRNA2, DEPDC5, KCNT1

Autosomal Dominant Lateral Temporal Lobe Epilepsy: LGI1, RELN

Benign Familial Neonatal or Infantile Seizures: KCNQ2, KCNQ3, PRRT2

Early-onset Absence Epilepsy: SLC2A1

Epilepsy and Mental Retardation Limited to Females: PCDH19

Rett Syndrome: MECP2, CDKL5, FOXG1

41 genes in which homozygous or compound heterozygous pathogenic variants have been reported to cause EIEE. Some of these genes are involved in well-characterized autosomal recessive conditions in which seizures are a predominant feature such as:

Neuronal Ceroid Lipofuscinosis: TPP1, PPT1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSF and KCTD7

Lafora Disease: EPM2A and NHLRC1

Selected metabolic disorders: FOLR1, GAMT, ALDH7A1, PNPO, SLC19A3

Selected mitochondrial disease: POLG, FARS2, SLC25A22

Gene Name Inherited Mode Treatment Related References
ALDH7A1 AR Bennett et al. 2009. PubMed ID: 19128417
BCKDK AR Oyarzabal et al. 2016. PubMed ID: 26809120
CHRNA4 AD Kurahashi and Hirose 2015. PubMed ID: 20301348
DEPDC5 AD Myers and Scheffer 2017. PubMed ID: 28406046
FOLR1 AR Steinfeld et al. 2009. PubMed ID: 19732866
GAMT AR Bodamer et al. 2009. PubMed ID: 19255414
GRIN2A AD Pierson et al 2014. PubMed ID: 24839611
KCNQ2 AD Sands et al. 2016. PubMed ID: 27888506
KCNQ3 AD Sands et al. 2016. PubMed ID: 27888506
KCNT1 AD Mikati et al 2015. PubMed ID: 26369628
PCDH19 AD Trivisano et al 2015. PubMed ID: 25510386
PNPO AR Bagci et al. 2007. PubMed ID: 18296573
POLG AR Hynynen et al 2014. PubMed ID: 25065347
PRRT2 AD Chou et al 2014. PubMed ID: 25520928
SCN1A AD Miller and Sotero de Menezes 2007. PubMed ID: 20301494.
SCN2A AD Wolff et al 2017. PubMed ID: 28379373
SCN8A AD Boerma et al 2016. PubMed ID: 26252990
SLC19A3 AR Tabarki et al. 2013. PubMed ID: 23269594
SLC2A1 AD Leen et al. 2010. PubMed ID: 20129935
STXBP1 AD Dilena et al 2016. PubMed ID: 26212315
TSC1 AD Palavra et al 2017. PubMed ID: 28386314
TSC2 AD Palavra et al 2017. PubMed ID: 28386314

See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for regions not captured or with insufficient number of sequence reads. All reported pathogenic, likely pathogenic, and variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

This panel typically provides >99% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

A full list of regions not covered by NGS or Sanger sequencing is available upon request.

Indications for Test

Testing is recommended for patients with symptoms of EIEE, notably those with infantile onset seizures with no clear structural or metabolic cause.

Diseases

Name Inheritance OMIM ID
Aminoacylase 1 Deficiency AR 609924
Amish Infantile Epilepsy Syndrome AR 609056
Basal Ganglia Disease, Biotin-Responsive AR 607483
Branched-chain ketoacid dehydrogenase kinase deficiency AR 614923
Cerebral Folate Deficiency AR 613068
Ceroid Lipofuscinosis Neuronal 1 AR 256730
Ceroid Lipofuscinosis Neuronal 10 AR 610127
Ceroid Lipofuscinosis Neuronal 13 AR 615362
Ceroid Lipofuscinosis Neuronal 2 AR 204500
Ceroid Lipofuscinosis Neuronal 3 AR 204200
Ceroid Lipofuscinosis Neuronal 4A, Autosomal Recessive AR 204300
Ceroid Lipofuscinosis Neuronal 5 AR 256731
Ceroid Lipofuscinosis Neuronal 6 AR 601780
Ceroid Lipofuscinosis Neuronal 7 AR 610951
Ceroid Lipofuscinosis Neuronal 8 AR 600143
Ceroid Lipofuscinosis Neuronal 8, Northern Epilepsy Variant AR 610003
Congenital Disorder of Glycosylation, Type IIm XL 300896
Cortical Dysplasia-Focal Epilepsy Syndrome AR 610042
Epilepsy, familial focal, with variable foci AD 604364
Epilepsy, Familial Focal, with Variable Foci 2 AD 617116
Epilepsy, Familial Temporal Lobe, 7 AD 616436
Epilepsy, focal, with speech disorder and with or without mental retardation AD 245570
Epilepsy, Lateral Temporal Lobe, Autosomal Dominant AD 600512
Epilepsy, Nocturnal Frontal Lobe, Type 1 AD 600513
Epilepsy, Nocturnal Frontal Lobe, Type 3 AD 605375
Epilepsy, Nocturnal Frontal Lobe, Type 4 AD 610353
Epilepsy, Progressive Myoclonic 3 AR 611726
Epilepsy, Progressive Myoclonic 4, With Or Without Renal Failure AR 254900
Epilepsy, Progressive Myoclonic 6 AR 614018
Epileptic encephalopathy, childhood-onset AD 615369
Epileptic encephalopathy, early infantile, 1 XLR 308350
Epileptic Encephalopathy, Early Infantile, 10 AR 613402
Epileptic Encephalopathy, Early Infantile, 11 AD 613721
Epileptic Encephalopathy, Early Infantile, 12 AR 613722
Epileptic Encephalopathy, Early Infantile, 13 AD 614558
Epileptic encephalopathy, early infantile, 14 AD 614959
Epileptic Encephalopathy, Early Infantile, 15 AR 615006
Epileptic Encephalopathy, Early Infantile, 16 AR 615338
Epileptic Encephalopathy, Early Infantile, 17 AD 615473
Epileptic encephalopathy, early infantile, 18 AR 615476
Epileptic Encephalopathy, Early Infantile, 2 XLD 300672
Epileptic Encephalopathy, Early Infantile, 24 AD 615871
Epileptic Encephalopathy, Early Infantile, 25 AR 615905
Epileptic Encephalopathy, Early Infantile, 26 AD 616056
Epileptic Encephalopathy, Early Infantile, 3 AR 609304
Epileptic Encephalopathy, Early Infantile, 32 AD 616366
Epileptic Encephalopathy, Early Infantile, 4 AD 612164
Epileptic Encephalopathy, Early Infantile, 5 AD 613477
Epileptic Encephalopathy, Early Infantile, 7 AD 613720
Epileptic Encephalopathy, Early Infantile, 8 XLR 300607
Epileptic Encephalopathy, Early Infantile, 9 XL 300088
Generalized Epilepsy With Febrile Seizures Plus, Type 1 AD 604233
Generalized Epilepsy With Febrile Seizures Plus, Type 3 AD 611277
Generalized Epilepsy With Febrile Seizures Plus, Type 7 AD 613863
Generalized Epilepsy with Febrile Seizures Plus, Type 9 AD 616172
Glut1 Deficiency Syndrome 1 AD 606777
Heterotopia, Periventricular, Autosomal Recessive AR 608097
Hyperphosphatasia with mental retardation syndrome 2 AR 614749
Kohlschutter-Tonz syndrome AR 226750
Lafora Disease AR 254780
Mental Retardation, Autosomal Dominant 1 AD 156200
Mental Retardation, Stereotypic Movements, Epilepsy, And/Or Cerebral Malformations AD 613443
Mental Retardation, X-Linked, Syndromic, Christianson Type XLD 300243
Myoclonic Epilepsy, Familial Infantile AR 605021
Pitt-Hopkins-like syndrome 2 AR 614325
Progressive Sclerosing Poliodystrophy AR 203700
Pyridoxine-Dependent Epilepsy AR 266100
Rett Syndrome, Congenital Variant IC 613454
Seizures, Benign Familial Infantile, 2 AD 605751
Seizures, Benign Familial Neonatal, 2 AD 121201
SeSAME Syndrome AR 612780
Spinocerebellar ataxia, autosomal recessive 12 AR 614322
Tuberous Sclerosis 1 AD 191100
Tuberous Sclerosis 2 AD 613254
Unverricht-Lundborg Syndrome AR 254800

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Epilepsy and Intellectual Disability in Females via the PCDH19 Gene
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Epilepsy: Benign Familial Neonatal Seizures Type 2 via the KCNQ3 Gene
Epilepsy: Early Infantile Epileptic Encephalopathy via the ARHGEF9 Gene
Epilepsy: Focal Epilepsy and Focal Cortical Dysplasia via the NPRL2 Gene
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Lissencephaly with Cerebellar Hypoplasia via the RELN Gene
Male Infertility Sequencing Panel with CNV Detection
Malignant Migrating Partial Seizures of Infancy and Autosomal Dominant Nocturnal Frontal Lobe Epilepsy via the KCNT1 Gene
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Neuronal Ceroid Lipofuscinosis 1 via the PPT1 Gene
Neuronal Ceroid Lipofuscinosis 10 via the CTSD Gene
Neuronal Ceroid Lipofuscinosis 13 via CTSF Gene Sequencing with CNV Detection
Neuronal Ceroid Lipofuscinosis 14 via the KCTD7 Gene
Neuronal Ceroid Lipofuscinosis 2 via the TPP1 Gene
Neuronal Ceroid Lipofuscinosis 3 (Batten Disease) via the CLN3 c.461-280_677+382 Deletion
Neuronal Ceroid Lipofuscinosis 3 via the CLN3 Gene
Neuronal Ceroid Lipofuscinosis 5 via the CLN5 Gene
Neuronal Ceroid Lipofuscinosis 6 via the CLN6 Gene
Neuronal Ceroid Lipofuscinosis 7 via the MFSD8 Gene
Neuronal Ceroid Lipofuscinosis 8 via the CLN8 Gene
Pendred Syndrome and Nonsyndromic Hearing Loss Associated with Enlarged Vestibular Aqueduct via the KCNJ10 Gene
Periventricular Heterotopia with Microcephaly via the ARFGEF2 Gene
Progressive Myoclonic Epilepsy via the GOSR2 Gene
Progressive Myoclonic Epilepsy, With or Without Renal Failure, via the SCARB2 Gene
Pyridoxine 5'-Phosphate Oxidase Deficiency via PNPO Gene Sequencing with CNV Detection
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Rett Syndrome via the MECP2 Gene
Rett Syndrome, Angelman Syndrome and Variant Syndromes Sequencing Panel with CNV Detection
Sodium Channel, Voltage-Gated, Type IX, Alpha Subunit Disorders via the SCN9A Gene
Spinocerebellar Ataxia-12 via the WWOX Gene
Tuberous Sclerosis Complex Sequencing Panel with CNV Detection
Tuberous Sclerosis Complex via the TSC1 Gene
Tuberous Sclerosis Complex via the TSC1 Gene
Tuberous Sclerosis Complex via the TSC2 Gene
Tuberous Sclerosis Complex via the TSC2 Gene
X-Linked Intellectual Disability Sequencing Panel with CNV Detection
X-Linked Lissencephaly-2 via ARX Gene Sequencing with CNV Detection

CONTACTS

Genetic Counselors
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Citations
  • Allen et al. 2013. PubMed ID: 23934111
  • Bagci et al. 2007. PubMed ID: 18296573
  • Bennett et al. 2009. PubMed ID: 19128417
  • Bodamer et al. 2009. PubMed ID: 19255414
  • Boerma et al 2016. PubMed ID: 26252990
  • Carvill et al. 2013. PubMed ID: 23708187
  • Carvill et al. 2014. PubMed ID: 24623842
  • Chou et al 2014. PubMed ID: 25520928
  • Della Mina et al. 2015. PubMed ID: 24848745
  • Dibbens et al. 2013. PubMed ID: 23542697
  • Dilena et al 2016. PubMed ID: 26212315
  • Gaily et al. 2013. PubMed ID: 23808377
  • Human Gene Mutation Database (Bio-base).
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  • Ishida et al. 2013. PubMed ID: 23542701
  • Khan and Al Baradie. 2012. PubMed ID: 23213494
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  • Miller and Sotero de Menezes 2007. PubMed ID: 20301494
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Order Kits
TEST METHODS

NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (http://www.hgvs.org).  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most cases, we are unable to determine the phase of sequence variants.  In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited.  Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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