Ataxia Panel

Updated
Summary
  • Is a 173 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion of ataxia when repeat expansion variants are excluded either as clinically incompatible or by previous testing.

Analysis methods
  • PLUS
Availability

4 weeks

Number of genes

173

Test code

NE2101

Panel size

Large

CPT codes
81479

Summary

The Blueprint Genetics Ataxia Panel (test code NE2101):

ICD codes

Commonly used ICD-10 code(s) when ordering the Ataxia Panel

ICD-10 Disease
G11.9 Cerebellar ataxia
G11.8 Spinocerebellar ataxia

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.

The hereditary ataxias including cerebellar ataxias, episodic ataxias and spinocerebellar ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. The episodic ataxias are characterized by periods of unsteady gait often associated with nystagmus or dysarthria. Myokymia, vertigo, or hearing loss may occur in some of the subtypes. The prevalence of the autosomal dominant cerebellar ataxias (ADCAs) is estimated to be approximately 1-5:100,000. Most ADCAs are spinocerebellar ataxias (SCA) or episodic ataxias. Autosomal recessive types of hereditary ataxia account for approximately 3:100,000 with Friedreich ataxia, ataxia-telangiectasia, and ataxia oculomotor apraxia being most common. Most of the spastic ataxias are recessively inherited.

Genes in the Ataxia Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCB7 Anemia, sideroblastic, and spinocerebellar ataxia XL 8 9
ABHD12 Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract AR 16 20
ACO2 Optic atrophy, Infantile cerebellar-retinal degeneration AR 16 15
ADCK3 Coenzyme Q10 deficiency, Progressive cerebellar ataxia and atrophy, Spinocerebellar ataxia AR 45 43
ADPRHL2 Neurodegeneration, childhood-onset, with brain atrophy AR 1
AFG3L2* Spastic ataxia, Spinocerebellar ataxia AD/AR 22 40
AGTPBP1 Neuropathy AR 3 1
AHI1 Joubert syndrome AR 62 93
ALDH5A1 Succinic semialdehyde dehydrogenase deficiency AR 16 70
ANO10 Spinocerebellar ataxia AR 19 18
APTX Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia AR 14 46
ARL13B Joubert syndrome AR 11 10
ARL6 Bardet-Biedl syndrome, Retinitis pigmentosa AR 14 21
ATCAY Ataxia, cerebellar, Cayman AR 1 3
ATM Breast cancer, Ataxia-Telangiectasia AD/AR 1047 1109
ATP1A3 Alternating hemiplegia of childhood, Dystonia 12 AD 79 112
ATP2B3 Spinocerebellar ataxia, X-linked 1 XL 6 7
ATP8A2 Dysequilibrium syndrome AR 9 11
BBS1 Bardet-Biedl syndrome AR 66 103
BBS10 Bardet-Biedl syndrome AR 90 107
BBS12 Bardet-Biedl syndrome AR 36 58
BBS2 Bardet-Biedl syndrome, Retinitis pigmentosa AR 58 91
BBS4 Bardet-Biedl syndrome AR 25 53
BBS5 Bardet-Biedl syndrome AR 18 31
BBS7 Bardet-Biedl syndrome AR 19 43
BBS9 Bardet-Biedl syndrome AR 27 52
BEAN1# Spinocerebellar ataxia AD 1 2
C10ORF2 Perrault syndrome, Mitochondrial DNA depletion syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 3 AR 37 80
C12ORF4 Autism spectrum disorder, Developmental delay with variable intellectual impairment and behavioral abnormalities AR 1 5
C5ORF42 Orofaciodigital syndrome, Joubert syndrome AR 97 103
CA8 Cerebellar ataxia, mental retardation, and dysequilibrium syndrome AR 4 4
CACNA1A Migraine, familial hemiplegic, Episodic ataxia, Spinocerebellar ataxia 6, Epileptic encephalopathy, early infantile, 42 AD 135 230
CACNA1G Spinocerebellar ataxia 42 8 11
CACNB4 Episodic ataxia, Epilepsy, idiopathic generalized, susceptibility to, 9 AD 2 7
CAMTA1 Cerebellar ataxia, nonprogressive, with mental retardation AD 38 8
CAPN1 Spastic paraplegia 76, autosomal recessive AR 6 16
CASK Mental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardation XL 87 112
CC2D2A# COACH syndrome, Joubert syndrome, Meckel syndrome AR 76 91
CCDC88C Spinocerebellar ataxia AD 6 10
CEP290* Bardet-Biedl syndrome, Leber congenital amaurosis, Joubert syndrome, Senior-Loken syndrome, Meckel syndrome AR 130 289
CEP41 Joubert syndrome AR/Digenic 7 11
CLCN2 Leukoencephalopathy with ataxia, Epilepsy AD/AR 30 36
CLN5 Neuronal ceroid lipofuscinosis, type 5 AR 62 47
CLPP Deafness AR 4 13
COA7 Spinocerebellar ataxia, Charcot-Marie-Tooth disease AR 2 7
COASY Neurodegeneration with brain iron accumulation 6 AR 3 3
COX20 Mitochondrial complex IV deficiency AR 4 1
CP* Aceruloplasminemia, Hypoceruloplasminemia AR 62 57
CSTB Epilepsy, progressive myoclonic AR 19 15
CWF19L1 Spinocerebellar ataxia AR 9 4
CYP27A1 Cerebrotendinous xanthomatosis AR 69 110
CYP2U1 Spastic paraplegia 56, autosomal recessive AR 14 19
DHPS# AR
DNAJC19 3-methylglutaconic aciduria AR 3 6
DNMT1 Neuropathy, hereditary sensory, Cerebellar ataxia, deafness, and narcolepsy AD 9 20
DOCK3 Ataxia AR 3 5
EBF3 Hypotonia, ataxia, and delayed development syndrome (HADDS) AD 32 26
EEF2 Spinocerebellar ataxia AD 1 2
ELOVL4 Stargardt disease, Icthyosis, spastic quadriplegia, and mental retardation, Spinocerebellar ataxia AD/AR 13 14
ELOVL5 Spinocerebellar ataxia AD 2 5
FA2H Spastic paraplegia AR 18 51
FBXL4 Mitochondrial DNA depletion syndrome AR 55 47
FDXR Auditory neuropathy and optic atrophy AR 5 19
FGF14 Spinocerebellar ataxia AD 9 10
FLVCR1 Ataxia, posterior column, with retinitis pigmentosa AR 9 15
FMR1 Premature ovarian failure, Fragile X syndrome, Fragile X tremor/ataxia syndrome XL 13 76
FXN* Friedreich ataxia AR 13 63
GBA2 Cerebellar ataxia with spasticity AR 11 22
GFAP Alexander disease AD 114 131
GOSR2* Epilepsy, progessive myoclonic AR 6 4
GRID2 Spinocerebellar ataxia AR 11 20
GRM1 Spinocerebellar ataxia AR 5 17
GSS Glutathione synthetase deficiency AR 8 38
HARS2 Perrault syndrome AR 7 3
HIBCH 3-hydroxyisobutryl-CoA hydrolase deficiency AR 18 16
INPP5E Joubert syndrome, Mental retardation, truncal obesity, retinal dystrophy, and micropenis (MORM syndrome) AR 25 50
IRF2BPL Neurodevelopmental disorder with hypotonia, seizures, and absent language AD 9 2
ITM2B Dementia, familial Danish, Retinal dystrophy with inner retinal dysfunction and ganglion cell abnormalities, Cerebral amyloid angiopathy AD 3 6
ITPR1 Spinocerebellar ataxia AD 35 89
KCNA1 Episodic ataxia/myokymia syndrome AD 24 45
KCNC3 Spinocerebellar ataxia AD 7 11
KCND3 Brugada syndrome, Spinocerebellar ataxia 19, Spinocerebellar ataxia 22 AD 7 29
KCNJ10 Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SESAME syndrome), Pendred syndrome, Enlarged vestibular aqueduct AR/Digenic 13 29
KIF1C* Spastic ataxia AR 7 17
KIF7 Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndrome AR/Digenic 24 44
LAMA1 Poretti-Boltshauser syndrome AR 32 40
LARS2 Perrault syndrome, Hydrops, lactic acidosis, and sideroblastic anemia (HLASA) AR 14 14
LMNB1 Leukodystrophy, demyelinating, adult-onset, autosomal dominant AD 2 35
LRPPRC Leigh syndrome, French-Canadian type AR 55 17
MARS2 Combined oxidative phosphorylation deficiency AR 8 5
MECR Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities (DYTOABG) AR 7 6
MKKS Bardet-Biedl syndrome, McKusick-Kaufman syndrome AR 21 59
MKS1 Bardet-Biedl syndrome, Meckel syndrome AR 50 52
MME Spinocerebellar ataxia 43, Charcot-Marie-Tooth disease, axonal, type 2T AD/AR 14 21
MRE11A Ataxia-telangiectasia-like disorder-1 AR 57 56
MSTO1#* Myopathy, mitochondrial, and ataxia AD/AR 7 8
MTFMT Combined oxidative phosphorylation deficiency 15 AR 15 16
MTPAP Spastic ataxia AR 1 2
MTTP Abetalipoproteinemia AR 12 69
NDUFAF6 Mitochondrial complex I deficiency, Leigh syndrome AR 18 10
NDUFS2 Mitochondrial complex I deficiency AR 5 24
NDUFS4 Mitochondrial complex I deficiency, Leigh syndrome AR 11 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 35
NKX6-2 Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy AR 4 8
NOL3 Myoclonus, familial cortical AD 1 3
NPHP1 Nephronophthisis, Joubert syndrome, Senior-Loken syndrome AR 19 76
NUBPL Mitochondrial complex I deficiency AR 9 10
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 153 160
OPA1 Optic atrophy, Optic atrophy 1, Optic atrophy with or without deafness, Ophthalmoplegia, myopathy, ataxia, and neuropathy, Behr synrome, Mitochondrial DNA depletion syndrome 14 AD/AR 96 390
OPHN1 Mental retardation, with cerebellar hypoplasia and distinctive facial appearance XL 28 42
PAX6 Aniridia, cerebellar ataxia, and mental retardation (Gillespie syndrome), Keratitis, Coloboma, ocular, Cataract with late-onset corneal dystrophy, Morning glory disc anomaly, Foveal hypoplasia, Aniridia, Optic nerve hypoplasia, Peters anomaly AD 144 550
PDYN Spinocerebellar ataxia AD 4 11
PEX7 Refsum disease, Rhizomelic CDP type 1 AR 44 53
PHYH Refsum disease AR 12 36
PNKD Paroxysmal non-kinesigenic dyskinesia AD 5 5
PNKP Epileptic encephalopathy, early infantile, Ataxia-oculomotor AR 34 23
PNPLA6 Laurence-Moon syndrome, Boucher-Neuhauser syndrome, Spastic paraplegia 39 AR 26 58
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 89 290
PRKCG Spinocerebellar ataxia AD/AR 28 47
PRRT2 Episodic kinesigenic dyskinesia, Seizures, benign familial infantile, 2, Convulsions, familial infantile, with paroxysmal choreoathetosis AD 42 99
PUM1 Ataxia AD 3 11
RNF216* Cerebellar ataxia and hypogonadotropic hypogonadism (Gordon Holmes syndrome) AR 10 14
RPGRIP1L# COACH syndrome, Joubert syndrome, Meckel syndrome, Retinal degeneration in ciliopathy, modifier AD/AR 39 49
RUBCN Spinocerebellar ataxia AR 4 4
SACS Spastic ataxia, Charlevoix-Saguenay AR 254 262
SCYL1 Spinocerebellar ataxia, autosomal recessive 21 AR 12 6
SERAC1 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome AR 22 52
SETX Ataxia with oculomotor apraxia, Amyotrophic lateral sclerosis, juvenile, Spinocerebellar ataxia AD/AR 36 210
SIL1 Marinesco-Sjogren syndrome AR 14 49
SLC1A3 Episodic ataxia AD 2 17
SLC20A2 Basal ganglia calcification, idiopathic, 1 AD 22 71
SLC25A46 Neuropathy, hereditary motor and sensory, type VIB AR 14 17
SLC2A1 Stomatin-deficient cryohydrocytosis with neurologic defects, Epilepsy, idiopathic generalized, GLUT1 deficiency syndrome AD/AR 106 275
SLC52A2 Brown-Vialetto-Van Laere syndrome AR 27 25
SLC9A1 Spinocerebellar ataxia, autosomal recessive 19 (Lichtenstein-Knorr syndrome) AR 2 4
SLC9A6 Mental retardation, syndromic, Christianson XL 24 28
SNX14 Spinocerebellar ataxia AR 15 18
SPG7 Spastic paraplegia AR 69 111
SPTBN2 Spinocerebellar ataxia AD/AR 18 28
STUB1 Spinocerebellar ataxia AR 13 28
SYNE1 Spinocerebellar ataxia, autosomal recessive 8 AD/AR 83 136
SYT14#* Spinocerebellar ataxia AR 5 3
TCTN1# Joubert syndrome AR 6 6
TCTN2 Joubert syndrome, Meckel syndrome AR 20 15
TCTN3 Orofaciodigital syndrome (Mohr-Majewski syndrome), Joubert syndrome AR 9 12
TDP1 Spinocerebellar ataxia, with axonal neuropathy AR 1 3
TGM6 Spinocerebellar ataxia AD 8 24
TMEM138 Joubert syndrome AR 6 8
TMEM216 Joubert syndrome, Meckel syndrome AR 17 8
TMEM231 Joubert syndrome, Meckel syndrome AR 12 19
TMEM237 Joubert syndrome AR 7 11
TMEM240 Spinocerebellar ataxia AD 8 6
TMEM67 Nephronophthisis, COACH syndrome, Joubert syndrome, Meckel syndrome AR 87 170
TPP1 Spinocerebellar ataxia, Neuronal ceroid lipofuscinosis type 2 AR 75 112
TRIM32 Bardet-Biedl syndrome, Muscular dystrophy, limb-girdle AR 13 16
TTBK2 Spinocerebellar ataxia AD 4 9
TTC19 Mitochondrial complex III deficiency, nuclear type 2 AR 13 10
TTC8 Bardet-Biedl syndrome, Retinitis pigmentosa AR 5 16
TTPA Ataxia with isolated vitamin E deficiency AR 29 30
TUBB4A* Leukodystrophy, hypomyelinating, Dystonia AD 39 42
UBA5* Epileptic encephalopathy, early infantile, 44, Spinocerebellar ataxia, autosomal recessive 24 AR 16 15
UBTF Neurodegeneration, childhood-onset, with brain atrophy AR 3 1
UCHL1 Parkinson disease 5, autosomal dominant, Spastic paraplegia 79, autosomal recessive AD/AR 5 5
VAMP1 Spastic ataxia AD 3 6
VLDLR Cerebellar ataxia, mental retardation, and dysequilibrium syndrome AR 11 24
WDPCP Meckel-Gruber syndrome, modifier, Bardet-Biedl syndrome, Congenital heart defects, hamartomas of tongue, and polysyndactyly AR 6 8
WDR81 Dysequilibrium syndrome AR 8 17
WFS1 Wolfram syndrome, Deafness, Wolfram-like syndrome, autosomal dominant, Deafness, autosomal dominant 6/14/38, Cataract 41 AD/AR 69 362
WWOX Epileptic encephalopathy, early infantile, Spinocerebellar ataxia AR 43 45
ZFYVE26 Spastic paraplegia 15 AR 63 39
ZNF423 Nephronophthisis, Joubert syndrome AD/AR 10 7

* 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 Ataxia Panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ADCK3 Chr1:227174508 c.*72dupG NM_020247.4
ATM Chr11:108093770 c.-174A>G NM_000051.3
ATM Chr11:108094508 c.-31+595G>A NM_000051.3
ATM Chr11:108098321 c.-30-1G>T NM_000051.3 rs869312754
ATM Chr11:108138753 c.2639-384A>G NM_000051.3
ATM Chr11:108141209 c.2839-579_2839-576delAAGT NM_000051.3
ATM Chr11:108151710 c.3403-12T>A NM_000051.3 rs201370733
ATM Chr11:108158168 c.3994-159A>G NM_000051.3 rs864622543
ATM Chr11:108164028 c.4612-12A>G NM_000051.3
ATM Chr11:108179837 c.5763-1050A>G NM_000051.3 rs774925473
ATM Chr11:108214779 c.8418+681A>G NM_000051.3 rs748635985
BBS1 Chr11:66291105 c.951+58C>T NM_024649.4
BBS4 Chr15:73001820 c.77-216delA NM_033028.4 rs113994189
BBS5 Chr2:170354110 c.619-27T>G NM_152384.2
CACNA1A Chr19:13317355 c.*1500_*1504dupCTTTT NM_001127221.1
CACNA1A Chr19:13341036 c.5404-13G>A NM_001127221.1
CACNA1A Chr19:13617793 NM_001127221.1 rs965852937
CEP290 Chr12:88462434 c.6012-12T>A NM_025114.3 rs752197734
CEP290 Chr12:88494960 c.2991+1655A>G NM_025114.3 rs281865192
CEP290 Chr12:88508350 c.1910-11T>G NM_025114.3
CEP290 Chr12:88534822 c.103-18_103-13delGCTTTT NM_025114.3
FMR1 ChrX:147031110 c.*746T>C NM_002024.5 rs183130936
GSS Chr20:33537864 c.129+1663A>G NM_000178.2 rs1474111175
GSS Chr20:33543525 c.-9+5G>A NM_000178.2
KCNJ10 Chr1:160039811 c.-1+1G>T NM_002241.4 rs796052606
MTTP Chr4:100512792 c.619-5_619-2delTTTA NM_000253.2 rs755155385
MTTP Chr4:100522736 c.1237-28A>G NM_000253.2
NDUFAF6 Chr8:96046914 c.298-768T>C NM_152416.3 rs575462405
NDUFAF6 Chr8:96048588 c.420+784C>T NM_152416.3 rs749738738
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
OFD1 ChrX:13773249 c.1130-20_1130-16delTTGGT NM_003611.2
OPA1 Chr3:193334932 c.449-34dupA NM_130837.2
OPA1 Chr3:193374829 c.2179-40G>C NM_130837.2
PAX6 Chr11:31685945 c.*125537G>T NM_000280.4 rs606231388
PAX6 Chr11:31812434 c.1033-42_1033-26delATGTGTTCCTCAGTAACinsG NM_000280.4
PAX6 Chr11:31816377 c.524-41T>G NM_000280.4
PAX6 Chr11:31823338 c.142-14C>G NM_000280.4 rs1131692291
PAX6 Chr11:31828391 c.-52+5delG NM_000280.4
PAX6 Chr11:31828391 c.-52+3_-52+6delAAGTinsTG NM_000280.4
PAX6 Chr11:31828392 c.-52+3_-52+4delAA NM_000280.4
PAX6 Chr11:31828395 c.-52+1delG NM_000280.4
PAX6 Chr11:31828396 c.-52+1G>A NM_000280.4
PAX6 Chr11:31828456 c.-115_-112delACTA NM_000280.4 rs1011844558
PAX6 Chr11:31828461 c.-118_-117delTT NM_000280.4
PAX6 Chr11:31828469 c.-125dupG NM_000280.4
PAX6 Chr11:31828474 c.-128-1G>T NM_000280.4
PAX6 Chr11:31828474 c.-128-2delA NM_000280.4 rs1131692282
PAX6 Chr11:31832372 c.-138_-129+3delCCTCATAAAGGTG NM_000280.4
PAX6 Chr11:31832374 c.-129+2T>A NM_000280.4
PAX6 Chr11:31832375 c.-129+1G>A NM_000280.4
PEX7 Chr6:137143759 c.-45C>T NM_000288.3 rs267608252
PNKP Chr19:50364799 c.1387-33_1386+49delCCTCCTCCCCTGACCCC NM_007254.3 rs752902474
PRRT2 Chr16:29825620 c.*345G>A NM_001256443.1
SERAC1 Chr6:158576548 c.92-165C>T NM_032861.3
SERAC1 Chr6:158576622 c.92-239G>C NM_032861.3
SIL1 Chr5:138283180 c.1030-18G>A NM_022464.4 rs769052639
SLC20A2 Chr8:42328683 c.289+937G>A NM_006749.4
SLC2A1 Chr1:43395462 c.680-11G>A NM_006516.2
SLC2A1 Chr1:43424429 c.-107G>A NM_006516.2
SLC52A2 Chr8:145582843 c.-110-1G>A NM_024531.4
STUB1 Chr16:732729 c.*240T>C NM_005861.2
SYNE1 Chr6:152640163 c.16237-13C>G NM_182961.3
SYNE1 Chr6:152643033 c.15918-12A>G NM_182961.3 rs606231134
TMEM231 Chr16:75575364 c.824-11T>C NM_001077416.2
TPP1 Chr11:6637752 c.887-18A>G NM_000391.3
TTC19 Chr17:15903121 c.-42G>T NM_017775.3 rs769078093
WFS1 Chr4:6271704 c.-43G>T NM_006005.3

Added and removed genes from the panel

Genes added Genes removed
ADPRHL2
AGTPBP1
ATP2B3
C12ORF4
CACNA1G
COA7
DHPS
DOCK3
IRF2BPL
MECR
MSTO1
NKX6-2
PUM1
SCYL1
SLC9A1
UBTF
UCHL1
PPP2R2B

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

Repeat expansion variants are not detected by this panel. The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: BEAN1 (NM_001178020:5), CC2D2A (NM_020785:7), DHPS (NM_001206974:1), RPGRIP1L (NM_015272:23), SYT14 (NM_001146261:3), TCTN1 (NM_001173976:2;NM_024549:6). 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 96.9% (7,563/7,806) >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%
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
     
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%

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 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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