Ataxia Panel

Last modified: Jun 12, 2018


  • Is a 157 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
  • SEQ


3-4 weeks

Number of genes


Test code


CPT codes

SEQ 81405
SEQ 81406
SEQ 81407
DEL/DUP 81479


The Blueprint Genetics Ataxia Panel (test code NE2101):

  • Is a 157 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

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

  • 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.

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 14 18
ACO2 Optic atrophy, Infantile cerebellar-retinal degeneration AR 16 13
ADCK3 Coenzyme Q10 deficiency, Progressive cerebellar ataxia and atrophy, Spinocerebellar ataxia AR 44 39
AFG3L2* Spastic ataxia, Spinocerebellar ataxia AD/AR 21 38
AHI1 Joubert syndrome AR 58 90
ALDH5A1 Succinic semialdehyde dehydrogenase deficiency AR 14 69
ANO10 Spinocerebellar ataxia AR 18 16
APTX Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia AR 14 42
ARL6 Bardet-Biedl syndrome, Retinitis pigmentosa AR 13 21
ARL13B Joubert syndrome AR 10 10
ATCAY Ataxia, cerebellar, Cayman AR 1 2
ATM Breast cancer, Ataxia-Telangiectasia AD/AR 860 1026
ATP1A3 Alternating hemiplegia of childhood, Dystonia 12 AD 80 106
ATP8A2 Dysequilibrium syndrome AR 9 10
BBS1 Bardet-Biedl syndrome AR 49 103
BBS2 Bardet-Biedl syndrome, Retinitis pigmentosa AR 35 90
BBS4 Bardet-Biedl syndrome AR 21 52
BBS5 Bardet-Biedl syndrome AR 14 30
BBS7 Bardet-Biedl syndrome AR 16 39
BBS9 Bardet-Biedl syndrome AR 24 51
BBS10 Bardet-Biedl syndrome AR 59 100
BBS12 Bardet-Biedl syndrome AR 12 57
BEAN1 Spinocerebellar ataxia AD 1 2
C5ORF42 Orofaciodigital syndrome, Joubert syndrome AR 84 100
C10ORF2 Perrault syndrome, Mitochondrial DNA depletion syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 3 AR 36 77
CA8 Cerebellar ataxia, mental retardation, and dysequilibrium syndrome AR 3 4
CACNA1A Migraine, familial hemiplegic, Episodic ataxia, Spinocerebellar ataxia 6, Epileptic encephalopathy, early infantile, 42 AD 121 211
CACNB4 Episodic ataxia, Epilepsy, idiopathic generalized, susceptibility to, 9 AD 2 7
CAMTA1 Cerebellar ataxia, nonprogressive, with mental retardation AD 32 7
CAPN1 Spastic paraplegia 76, autosomal recessive AR 6 14
CASK Mental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardation XL 80 104
CC2D2A COACH syndrome, Joubert syndrome, Meckel syndrome AR 75 90
CCDC88C Spinocerebellar ataxia AD 6 7
CEP41 Joubert syndrome AR/Digenic 7 10
CEP290* Bardet-Biedl syndrome, Leber congenital amaurosis, Joubert syndrome, Senior-Loken syndrome, Meckel syndrome AR 117 280
CLCN2 Leukoencephalopathy with ataxia, Epilepsy AD/AR 25 23
CLN5 Neuronal ceroid lipofuscinosis, type 5 AR 49 45
CLPP Deafness AR 3 13
COASY Neurodegeneration with brain iron accumulation 6 AR 3 3
COX20 Mitochondrial complex IV deficiency AR 4 1
CP* Aceruloplasminemia, Hypoceruloplasminemia AR 55 51
CSTB Epilepsy, progressive myoclonic AR 18 15
CWF19L1 Spinocerebellar ataxia AR 9 4
CYP2U1 Spastic paraplegia 56, autosomal recessive AR 12 17
CYP27A1 Cerebrotendinous xanthomatosis AR 61 108
DNAJC19 3-methylglutaconic aciduria AR 3 5
DNMT1 Neuropathy, hereditary sensory, Cerebellar ataxia, deafness, and narcolepsy AD 9 19
EBF3 Hypotonia, ataxia, and delayed development syndrome (HADDS) AD 29 25
EEF2 Spinocerebellar ataxia AD 1 1
ELOVL4 Stargardt disease, Icthyosis, spastic quadriplegia, and mental retardation, Spinocerebellar ataxia AD/AR 11 12
ELOVL5 Spinocerebellar ataxia AD 2 3
FA2H Spastic paraplegia AR 17 41
FBXL4 Mitochondrial DNA depletion syndrome AR 55 47
FDXR Auditory neuropathy and optic atrophy AR 5 17
FGF14 Spinocerebellar ataxia AD 7 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 12 63
GBA2 Cerebellar ataxia with spasticity AR 10 16
GFAP Alexander disease AD 114 131
GOSR2* Epilepsy, progessive myoclonic AR 5 2
GRID2 Spinocerebellar ataxia AR 11 18
GRM1 Spinocerebellar ataxia AR 5 17
GSS Glutathione synthetase deficiency AR 8 34
HARS2 Perrault syndrome AR 7 3
HIBCH 3-hydroxyisobutryl-CoA hydrolase deficiency AR 19 13
INPP5E Joubert syndrome, Mental retardation, truncal obesity, retinal dystrophy, and micropenis (MORM syndrome) AR 24 48
ITM2B Dementia, familial Danish, Retinal dystrophy with inner retinal dysfunction and ganglion cell abnormalities, Cerebral amyloid angiopathy AD 3 3
ITPR1 Spinocerebellar ataxia AD 32 76
KCNA1 Episodic ataxia/myokymia syndrome AD 24 41
KCNC3 Spinocerebellar ataxia AD 6 9
KCND3 Brugada syndrome, Spinocerebellar ataxia 19, Spinocerebellar ataxia 22 AD 7 24
KCNJ10 Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SESAME syndrome), Pendred syndrome, Enlarged vestibular aqueduct AR/Digenic 14 25
KIF1C* Spastic ataxia AR 6 9
KIF7 Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndrome AR/Digenic 23 40
LAMA1 Poretti-Boltshauser syndrome AR 27 37
LARS2 Perrault syndrome, Hydrops, lactic acidosis, and sideroblastic anemia (HLASA) AR 14 11
LMNB1 Leukodystrophy, demyelinating, adult-onset, autosomal dominant AD 2 34
LRPPRC Leigh syndrome, French-Canadian type AR 20 15
MARS2 Combined oxidative phosphorylation deficiency AR 8 5
MKKS Bardet-Biedl syndrome, McKusick-Kaufman syndrome AR 18 59
MKS1 Bardet-Biedl syndrome, Meckel syndrome AR 43 52
MME Spinocerebellar ataxia 43, Charcot-Marie-Tooth disease, axonal, type 2T AD/AR 14 19
MRE11A Ataxia-telangiectasia-like disorder-1 AR 57 51
MTFMT Combined oxidative phosphorylation deficiency 15 AR 15 16
MTPAP Spastic ataxia AR 1 2
MTTP Abetalipoproteinemia AR 11 68
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
NOL3 Myoclonus, familial cortical AD 1 2
NPHP1 Nephronophthisis, Joubert syndrome, Senior-Loken syndrome AR 16 73
NUBPL Mitochondrial complex I deficiency AR 10 9
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 142 157
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 97 387
OPHN1 Mental retardation, with cerebellar hypoplasia and distinctive facial appearance XL 25 36
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 130 518
PDYN Spinocerebellar ataxia AD 4 11
PEX7 Refsum disease, Rhizomelic CDP type 1 AR 37 52
PHYH Refsum disease AR 11 36
PNKD Paroxysmal non-kinesigenic dyskinesia AD 4 3
PNKP Epileptic encephalopathy, early infantile, Ataxia-oculomotor AR 34 17
PNPLA6 Laurence-Moon syndrome, Boucher-Neuhauser syndrome, Spastic paraplegia 39 AR 25 50
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
PPP2R2B Spinocerebellar ataxia AD 1 5
PRKCG Spinocerebellar ataxia AD/AR 28 43
PRRT2 Episodic kinesigenic dyskinesia, Seizures, benign familial infantile, 2, Convulsions, familial infantile, with paroxysmal choreoathetosis AD 40 93
RNF216* Cerebellar ataxia and hypogonadotropic hypogonadism (Gordon Holmes syndrome) AR 10 12
RPGRIP1L COACH syndrome, Joubert syndrome, Meckel syndrome, Retinal degeneration in ciliopathy, modifier AD/AR 36 45
RUBCN Spinocerebellar ataxia AR 4 4
SACS Spastic ataxia, Charlevoix-Saguenay AR 131 239
SERAC1 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome AR 23 48
SETX Ataxia with oculomotor apraxia, Amyotrophic lateral sclerosis, juvenile, Spinocerebellar ataxia AD/AR 35 194
SIL1 Marinesco-Sjogren syndrome AR 14 49
SLC1A3 Episodic ataxia AD 2 14
SLC2A1 Stomatin-deficient cryohydrocytosis with neurologic defects, Epilepsy, idiopathic generalized, GLUT1 deficiency syndrome AD/AR 98 262
SLC9A6 Mental retardation, syndromic, Christianson XL 24 21
SLC20A2 Basal ganglia calcification, idiopathic, 1 AD 19 67
SLC25A46 Neuropathy, hereditary motor and sensory, type VIB AR 12 13
SLC52A2 Brown-Vialetto-Van Laere syndrome AR 26 22
SNX14 Spinocerebellar ataxia AR 15 14
SPG7 Spastic paraplegia AR 64 108
SPTBN2 Spinocerebellar ataxia AD/AR 17 21
STUB1 Spinocerebellar ataxia AR 13 27
SYNE1 Spinocerebellar ataxia, autosomal recessive 8 AD/AR 73 118
SYT14* Spinocerebellar ataxia AR 5 2
TCTN1 Joubert syndrome AR 6 6
TCTN2 Joubert syndrome, Meckel syndrome AR 19 13
TCTN3 Orofaciodigital syndrome (Mohr-Majewski syndrome), Joubert syndrome AR 9 10
TDP1 Spinocerebellar ataxia, with axonal neuropathy AR 1 2
TGM6 Spinocerebellar ataxia AD 6 20
TMEM67 Nephronophthisis, COACH syndrome, Joubert syndrome, Meckel syndrome AR 87 157
TMEM138 Joubert syndrome AR 6 8
TMEM216 Joubert syndrome, Meckel syndrome AR 13 8
TMEM231 Joubert syndrome, Meckel syndrome AR 11 19
TMEM237 Joubert syndrome AR 7 11
TMEM240 Spinocerebellar ataxia AD 8 6
TPP1 Spinocerebellar ataxia, Neuronal ceroid lipofuscinosis type 2 AR 56 110
TRIM32 Bardet-Biedl syndrome, Muscular dystrophy, limb-girdle AR 13 16
TTBK2 Spinocerebellar ataxia AD 4 7
TTC8 Bardet-Biedl syndrome, Retinitis pigmentosa AR 5 16
TTC19 Mitochondrial complex III deficiency, nuclear type 2 AR 13 9
TTPA Ataxia with isolated vitamin E deficiency AR 27 28
TUBB4A* Leukodystrophy, hypomyelinating, Dystonia AD 39 40
UBA5* Epileptic encephalopathy, early infantile, 44, Spinocerebellar ataxia, autosomal recessive 24 AR 16 14
VAMP1 Spastic ataxia AD 2 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 5 7
WDR81 Dysequilibrium syndrome AR 8 16
WFS1 Wolfram syndrome, Deafness, Wolfram-like syndrome, autosomal dominant, Deafness, autosomal dominant 6/14/38, Cataract 41 AD/AR 68 351
WWOX Epileptic encephalopathy, early infantile, Spinocerebellar ataxia AR 38 42
ZFYVE26 Spastic paraplegia 15 AR 26 38
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).

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
ATM Chr11:108093770 c.-174A>G NM_000051.3
ATM Chr11:108098321 c.-30-1G>T NM_000051.3 rs869312754
ATM Chr11:108094508 c.-31+595G>A NM_000051.3
ATM Chr11:108121024 c.1236-404C>T NM_000051.3
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 Chr11:108179837 c.5763-1050A>G NM_000051.3 rs774925473
BBS1 Chr11:66291682 c.1110+329C>T NM_024649.4 rs571170303
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 Chr19:13341036 c.5404-13G>A NM_001127221.1
CEP290 Chr12:88494960 c.2991+1655A>G NM_025114.3 rs281865192
CEP290 Chr12:88462434 c.6012-12T>A NM_025114.3 rs752197734
GSS Chr20:33543525 c.-9+5G>A NM_000178.2
KCNJ10 Chr1:160039811 c.-1+1G>T NM_002241.4 rs796052606
MTTP Chr4:100522736 c.1237-28A>G NM_000253.2
MTTP Chr4:100512792 c.619-5_619-2delTTTA NM_000253.2 rs755155385
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
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
OPA1 Chr3:193374829 c.2179-40G>C NM_130837.2
OPA1 Chr3:193335986 c.610+360G>A NM_130837.2
OPA1 Chr3:193335990 c.610+364G>A NM_130837.2
PAX6 Chr11:31685945 c.*125537G>T NM_000280.4 rs606231388
PAX6 Chr11:31828474 c.-128-1G>T NM_000280.4
PAX6 Chr11:31832374 c.-129+2T>A NM_000280.4
PAX6 Chr11:31828396 c.-52+1G>A NM_000280.4
PAX6 Chr11:31816377 c.524-41T>G 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
SIL1 Chr5:138283180 c.1030-18G>A NM_022464.4 rs769052639
SLC2A1 Chr1:43395462 c.680-11G>A NM_006516.2
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
WFS1 Chr4:6271704 c.-43G>T NM_006005.3

Added and removed genes from the panel

Genes added Genes removed

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

Repeat expansion variants are not detected by this panel. 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. 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
  • 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 ataxia panel covers classical genes associated with cerebellar ataxia, spinocerebellar ataxia and episodic ataxia. 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%


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. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

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.