Ataxia Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: NE2101

The Blueprint Genetics Ataxia Panel is a 141 gene test for genetic diagnostics of patients with clinical suspicion of cerebellar ataxia, episodic ataxia or spinocerebellar ataxia.

Hereditary ataxia can be inherited in an autosomal recessive, autosomal dominant or X-linked manner. The clinical utility of a multi-gene panel for diagnosis of hereditary ataxias has been shown to be efficient, cost effective and enabled a molecular diagnosis in many refractory cases (PMID: 24030952). By sequencing 58 known human ataxia genes in 50 heterogeneous patients with ataxia who had been extensively investigated and were refractory to diagnosis, the overall detection rate of 18% was achieved. It was 40% in those with a childhood or adolescent onset progressive disorder and 75% in those with an adolescent onset and a family history.

About Ataxia

The hereditary 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. Permanent ataxia and even cerebellar atrophy may result late in the disease course. Prevalence of the autosomal dominant cerebellar ataxias (ADCAs) is estimated to be approximately 1-5:100,000. Often, one autosomal dominant ataxia cannot be differentiated from another because the most frequent manifestations of all of AD ataxias are progressive adult-onset gait ataxia and dysarthria associated with cerebellar atrophy on brain imaging; secondly, the ages of onset often overlap. 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.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

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 12 18
ACO2 Optic atrophy, Infantile cerebellar-retinal degeneration AR 13 13
ADCK3 Coenzyme Q10 deficiency, Progressive cerebellar ataxia and atrophy, Spinocerebellar ataxia AR 40 37
AFG3L2* Spastic ataxia, Spinocerebellar ataxia AD/AR 21 37
AHI1 Joubert syndrome AR 53 84
ALDH5A1 Succinic semialdehyde dehydrogenase deficiency AR 10 69
ANO10 Spinocerebellar ataxia AR 15 16
APTX Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia AR 14 40
ARL6 Bardet-Biedl syndrome, Retinitis pigmentosa AR 13 21
ARL13B Joubert syndrome AR 9 9
ATCAY Ataxia, cerebellar, Cayman AR 1 2
ATM Breast cancer, Ataxia-Telangiectasia AD/AR 646 923
ATN1 Dentatorubro-pallidoluysian atrophy AD 4 4
ATP8A2 Dysequilibrium syndrome AR 7 8
ATXN1 Spinocerebellar ataxia AD 4 5
ATXN2 Spinocerebellar ataxia AD 1 32
ATXN3 Spinocerebellar ataxia (Machado-Joseph disease) AD 2 3
ATXN7 Spinocerebellar ataxia AD 1 4
ATXN10 Spinocerebellar ataxia AD 5 4
BBS1 Bardet-Biedl syndrome AR 48 100
BBS2 Bardet-Biedl syndrome, Retinitis pigmentosa AR 32 90
BBS4 Bardet-Biedl syndrome AR 20 51
BBS5 Bardet-Biedl syndrome AR 14 30
BBS7 Bardet-Biedl syndrome AR 14 39
BBS9 Bardet-Biedl syndrome AR 22 49
BBS10 Bardet-Biedl syndrome AR 54 98
BBS12 Bardet-Biedl syndrome AR 11 57
BEAN1 Spinocerebellar ataxia AD 1 2
C5ORF42 Orofaciodigital syndrome, Joubert syndrome AR 68 98
C10ORF2 Perrault syndrome, Mitochondrial DNA depletion syndrome AR 37
CA8 Cerebellar ataxia, mental retardation, and dysequilibrium syndrome AR 2 4
CACNA1A Migraine, familial hemiplegic, Episodic ataxia AD 93 203
CACNB4 Episodic ataxia AD 2 7
CAMTA1 Cerebellar ataxia, nonprogressive, with mental retardation AD 27 7
CASK Mental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardation XL 67 87
CC2D2A COACH syndrome, Joubert syndrome, Meckel syndrome AR 71 86
CCDC28B Bardet-Biedl syndrome, modifier AD
CCDC88C Spinocerebellar ataxia AD 6 6
CEP41 Joubert syndrome AR/Digenic 7 10
CEP290* Bardet-Biedl syndrome, Leber congenital amaurosis, Joubert syndrome, Senior-Loken syndrome, Meckel syndrome AR 96 266
CLCN2 Leukoencephalopathy with ataxia, Epilepsy AD/AR 19 22
CLN5 Ceroid lipofuscinosis, neuronal AR 47 43
CLPP Deafness AR 3 13
COX20 Mitochondrial complex IV deficiency AR 4 1
CSTB Epilepsy, progressive myoclonic AR 17 15
CWF19L1 Spinocerebellar ataxia AR 6 4
CYP27A1 Cerebrotendinous xanthomatosis AR 57 108
DNAJC19 3-methylglutaconic aciduria AR 3 3
DNMT1 Neuropathy, hereditary sensory, Cerebellar ataxia, deafness, and narcolepsy AD 10 19
EEF2 Spinocerebellar ataxia AD 1 1
ELOVL4 Stargardt disease, Icthyosis, spastic quadriplegia, and mental retardation, Spinocerebellar ataxia AD/AR 10 12
ELOVL5 Spinocerebellar ataxia AD 2 3
FBXL4 Mitochondrial DNA depletion syndrome AR 54 36
FGF14 Spinocerebellar ataxia AD 6 10
FLVCR1 Ataxia, posterior column, with retinitis pigmentosa AR 6 15
FMR1 Premature ovarian failure XL 13 76
FXN* Friedreich ataxia AR 11 62
GBA2 Cerebellar ataxia with spasticity AR 9 16
GFAP Alexander disease AD 114 128
GOSR2* Epilepsy, progessive myoclonic AR 5 2
GRID2 Spinocerebellar ataxia AR 11 16
GRM1 Spinocerebellar ataxia AR 5 14
GSS Glutathione synthetase deficiency AR 7 34
HARS2 Perrault syndrome AR 7 3
HTT Huntington disease AD 8 7
INPP5E Joubert syndrome, Mental retardation, truncal obesity, retinal dystrophy, and micropenis (MORM syndrome) AR 23 44
ITM2B Dementia, familial Danish, Retinal dystrophy with inner retinal dysfunction and ganglion cell abnormalities, Cerebral amyloid angiopathy AD 3 3
ITPR1 Spinocerebellar ataxia AD 29 73
KCNA1 Episodic ataxia/myokymia syndrome AD 22 40
KCNC3 Spinocerebellar ataxia AD 5 9
KCND3 Brugada syndrome AD 9 21
KCNJ10 Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SESAME syndrome), Pendred syndrome, Enlarged vestibular aqueduct AR/Digenic 14 24
KIF1C* Spastic ataxia AR 6 9
KIF7 Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndrome AR/Digenic 15 40
LAMA1 Poretti-Boltshauser syndrome AR 20 34
LARS2 Perrault syndrome AR 11 11
MARS2 Combined oxidative phosphorylation deficiency AR 7 5
MKKS Bardet-Biedl syndrome, McKusick-Kaufman syndrome AR 15 59
MKS1 Bardet-Biedl syndrome, Meckel syndrome AR 42 51
MRE11A Ataxia-telangiectasia-like disorder-1 AR 35 43
MTPAP Spastic ataxia AR 2 2
MTTP Abetalipoproteinemia AR 10 66
NEDD4 Spinocerebellar ataxia AD 1
NOL3 Myoclonus, familial cortical AD 1 2
NOP56 Spinocerebellar ataxia AD 2 1
NPHP1 Nephronophthisis, Joubert syndrome, Senior-Loken syndrome AR 14 73
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 133 156
OPA1 Optic atrophy AD/AR 80 372
OPHN1 Mental retardation, with cerebellar hypoplasia and distinctive facial appearance XL 23 35
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 106 473
PDYN Spinocerebellar ataxia AD 4 11
PEX7 Refsum disease, Rhizomelic CDP type 1 AR 36 52
PHYH Refsum disease AR 10 36
PNKD Paroxysmal non-kinesigenic dyskinesia AD 4 3
PNKP Epileptic encephalopathy, early infantile, Ataxia-oculomotor AR 31 17
PNPLA6 Laurence-Moon syndrome, Boucher-Neuhauser syndrome AR 22 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 92 274
PPP2R2B Spinocerebellar ataxia AD 1 5
PRKCG Spinocerebellar ataxia AD/AR 29 40
PRRT2 Episodic kinesigenic dyskinesia AD 33 93
RPGRIP1L COACH syndrome, Joubert syndrome, Meckel syndrome, Retinal degeneration in ciliopathy, modifier AD/AR 35 45
RUBCN Spinocerebellar ataxia AR 4 4
SACS Spastic ataxia, Charlevoix-Saguenay AR 116 234
SETX Ataxia with oculomotor apraxia, Amyotrophic lateral sclerosis, juvenile, Spinocerebellar ataxia AD/AR 27 190
SIL1 Marinesco-Sjogren syndrome AR 14 49
SLC1A3 Episodic ataxia AD 2 10
SLC2A1 Stomatin-deficient cryohydrocytosis with neurologic defects, Epilepsy, idiopathic generalized, GLUT1 deficiency syndrome AD/AR 82 259
SLC9A6 Mental retardation, syndromic, Christianson XL 22 19
SLC52A2 Brown-Vialetto-Van Laere syndrome AR 22 19
SNX14 Spinocerebellar ataxia AR 14 14
SPG7 Spastic paraplegia AR 53 104
SPTBN2 Spinocerebellar ataxia AD/AR 14 20
STUB1 Spinocerebellar ataxia AR 12 26
SYT14* Spinocerebellar ataxia AR 4 2
TBP Spinocerebellar ataxia AD/AR 1 17
TCTN1 Joubert syndrome AR 6 6
TCTN2 Joubert syndrome, Meckel syndrome AR 17 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 5 12
TMEM67 Nephronophthisis, COACH syndrome, Joubert syndrome, Meckel syndrome AR 82 153
TMEM138 Joubert syndrome AR 6 8
TMEM216 Joubert syndrome, Meckel syndrome AR 14 8
TMEM231 Joubert syndrome, Meckel syndrome AR 9 19
TMEM237 Joubert syndrome AR 6 10
TMEM240 Spinocerebellar ataxia AD 7 6
TPP1 Spinocerebellar ataxia, Neuronal ceroid lipofuscinosis type 2 AR 52 110
TRIM32 Bardet-Biedl syndrome, Muscular dystrophy, limb-girdle AR 11 16
TTBK2 Spinocerebellar ataxia AD 4 6
TTC8 Bardet-Biedl syndrome, Retinitis pigmentosa AR 5 16
TTPA Ataxia with isolated vitamin E deficiency AR 26 28
TUBB4A* Leukodystrophy, hypomyelinating, Dystonia AD 38 38
VAMP1 Spastic ataxia AD 1 6
VLDLR Cerebellar ataxia, mental retardation, and dysequilibrium syndrome AR 9 24
WDPCP Meckel-Gruber syndrome, modifier, Bardet-Biedl syndrome, Congenital heart defects, hamartomas of tongue, and polysyndactyly AR 6 7
WDR81 Dysequilibrium syndrome AR 7 4
WFS1 Wolfram syndrome, Deafness AD/AR 65 343
WWOX Epileptic encephalopathy, early infantile, Spinocerebellar ataxia AR 30 36
ZNF423 Nephronophthisis, Joubert syndrome AD/AR 10 7
ZNF592* Spinocerebellar ataxia AR 1

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number
ATM Chr11:108098321 c.-30-1G>T NM_000051.3 rs869312754
ATM Chr11:108141209 c.2839-579_2839-576delAAGT NM_000051.3
ATM Chr11:108179837 c.5763-1050A>G NM_000051.3 rs774925473
BBS4 Chr15:73001820 c.77-216delA NM_033028.4 rs113994189
CEP290 Chr12:88494960 c.2991+1655A>G NM_025114.3 rs281865192
KCNJ10 Chr1:160039811 c.-1+1G>T NM_002241.4 rs796052606
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
PAX6 Chr11:31832374 c.-129+2T>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

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

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
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

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.

Blueprint Genetics offers a comprehensive Ataxia Panel that covers classical genes associated with cerebellar ataxia, episodic ataxia and spinocerebellar ataxia. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes when ordering the Ataxia Panel

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

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

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