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Invitae Hereditary Spastic Paraplegia Comprehensive Panel
Test description
The Invitae Hereditary Spastic Paraplegia Comprehensive Panel analyzes up to 65 genes associated with hereditary spastic paraplegia (HSP). These genes include the most common causes of autosomal dominant, autosomal recessive, and X-linked HSP.
The clinical presentation of HSP is variable, and the Invitae Hereditary Spastic Paraplegia Comprehensive Panel may confirm a clinical diagnosis and identify a causative gene while avoiding costly and time-consuming sequential testing. This test is Invitae’s broadest HSP panel. Because this panel covers genes with dominant, recessive, and X-linked inheritance patterns, it is particularly helpful if the inheritance pattern is unclear based on the individual’s family history.
Genes tested
Primary panel
ABCD1 ALDH18A1 ALS2 AP4B1 AP4E1 AP4M1 AP4S1 AP5Z1 ATL1 B4GALNT1 BSCL2 C12orf65 CYP2U1 CYP7B1 DDHD1 DDHD2 ERLIN2 FA2H GBA2 GJC2 HEXA HSPD1 KDM5C KIF1A KIF1C KIF5A L1CAM NIPA1 NT5C2 PLP1 PNPLA6 REEP1 REEP2 RTN2 SACS SLC16A2 SPART SPAST SPG11 SPG21 SPG7 TECPR2 VAMP1 WASHC5 ZFYVE26
Add-on Preliminary-evidence Genes for Hereditary Spastic Paraplegia
AMPD2 ARL6IP1 ARSI ATP13A2 C19orf12 CCT5 CPT1C ENTPD1 ERLIN1 EXOSC3 IBA57 MAG PGAP1 RAB3GAP2 SLC33A1 TFG USP8 VPS37A ZFR ZFYVE27
Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.
Order test
Primary panel (45 genes)
Customized gene selection (0 included, 0 excluded)
ABCD1 ALDH18A1 ALS2 AP4B1 AP4E1 AP4M1 AP4S1 AP5Z1 ATL1 B4GALNT1 BSCL2 C12orf65 CYP2U1 CYP7B1 DDHD1 DDHD2 ERLIN2 FA2H GBA2 GJC2 HEXA HSPD1 KDM5C KIF1A KIF1C KIF5A L1CAM NIPA1 NT5C2 PLP1 PNPLA6 REEP1 REEP2 RTN2 SACS SLC16A2 SPART SPAST SPG11 SPG21 SPG7 TECPR2 VAMP1 WASHC5 ZFYVE26
Add-on Preliminary-evidence Genes for Hereditary Spastic Paraplegia (20 genes)
Customized gene selection (0 included, 0 excluded)
Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.
AMPD2 ARL6IP1 ARSI ATP13A2 C19orf12 CCT5 CPT1C ENTPD1 ERLIN1 EXOSC3 IBA57 MAG PGAP1 RAB3GAP2 SLC33A1 TFG USP8 VPS37A ZFR ZFYVE27
Alternative tests to consider
Hereditary spastic paraplegia may have overlapping features with other neurological disorders, in which case clinicians may consider Invitae’s Comprehensive Neuropathy panel, which additionally includes genes associated with Charcot-Marie-Tooth disease, Distal Hereditary Motor Neuropathy, and Hereditary Sensory and Autonomic Neuropathy.
Clinical information
Clinical description
Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that is subdivided into complicated (i.e., syndromic) and uncomplicated forms. All forms of HSP, complicated and uncomplicated, share the primary symptom of lower-extremity spastic weakness. Individuals with complicated HSP exhibit additional neurologic features such as intellectual disability, seizures, ataxia, peripheral neuropathy, deafness, cataracts, retinal degeneration, or muscle atrophy, depending on which gene is causative. Both types of HSP are caused by the dysfunction of axons in the corticospinal tract that carry signals to the lower extremities, and both types can be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern.
| Gene | Subtype | Inheritance | Clinical form | Associated syndromes and other related disorders | |||
|---|---|---|---|---|---|---|---|
| Autosomal dominant | Autosomal recessive | X-linked | Uncomplicated | Complicated | |||
| ABCD1 | ✓ | ✓ | adrenoleukodystrophy | ||||
| ALDH18A1 | SPG9A, SPG9B | ✓ | ✓ | ✓ | congenital cataracts, hearing loss, and neurodegeneration | ||
| ALS2 | IAHSP | ✓ | ✓ | amyotrophic lateral sclerosis, juvenile; Primary lateral sclerosis, juvenile | |||
| AMPD2* | SPG63 | ✓ | ✓ | pontocerebellar hypoplasia | |||
| AP4B1 | SPG47 | ✓ | ✓ | ||||
| AP4E1 | SPG51 | ✓ | ✓ | ||||
| AP4M1 | SPG50 | ✓ | ✓ | ||||
| AP4S1 | SPG52 | ✓ | ✓ | ||||
| AP5Z1 | SPG48 | ✓ | ✓ | ||||
| ARL6IP1* | SPG61 | ✓ | ✓ | ||||
| ARSI* | SPG66 | ✓ | ✓ | ||||
| ATL1 | SPG3A | ✓ | ✓ | hereditary sensory neuropathy | |||
| ATP13A2* | SPG78 | ✓ | ✓ | Kufor-Rakeb syndrome | |||
| B4GALNT1 | SPG26 | ✓ | ✓ | ||||
| BSCL2 | SPG17 | ✓ | ✓ | silver syndrome, type-V; distal hereditary motor neuropathy; Charcot-Marie-Tooth disease, type-2; Berardinelli-Seip congenital lipodystrophy | |||
| C12ORF65 | SPG55 | ✓ | ✓ | ||||
| C19orf12* | SPG43 | ✓ | ✓ | neurodegeneration with brain iron accumulation type 4 | |||
| CCT5* | ✓ | ✓ | hereditary sensory neruopathy with spastic paraplegia | ||||
| CPT1C* | SPG73 | ✓ | ✓ | ||||
| CYP2U1 | SPG56 | ✓ | ✓ | ||||
| CYP7B1 | SPG5 | ✓ | ✓ | ✓ | |||
| DDHD1 | SPG28 | ✓ | ✓ | ✓ | |||
| DDHD2 | SPG54 | ✓ | ✓ | ||||
| ENTPD1* | SPG64 | ✓ | ✓ | ||||
| ERLIN1* | SPG62 | ✓ | ✓ | ||||
| ERLIN2 | SPG18 | ✓ | ✓ | ||||
| EXOSC3* | ✓ | ✓ | pontocerebellar hypoplasia | ||||
| FA2H | SPG35 | ✓ | ✓ | ||||
| GBA2 | SPG46 | ✓ | ✓ | ||||
| GJC2 | SPG44 | ✓ | ✓ | hypomyelinating leukodystrophy; hereditary lymphedema | |||
| HEXA | ✓ | ✓ | Hexosaminidase A deficiency | ||||
| HSPD1 | SPG13 | ✓ | ✓ | MitCHAP-60 disease (hypomyelinating leukodystrophy) | |||
| IBA57* | SPG74 | ✓ | ✓ | ||||
| KDM5C | MRXSCJ | ✓ | ✓ | X-linked Intellectual disability, Claes-Jensen type | |||
| KIF1A | SPG30 | ✓ | ✓ | ✓ | ✓ | ||
| KIF1C | SPAX2 | ✓ | ✓ | spastic ataxia 2 | |||
| KIF5A | SPG10 | ✓ | ✓ | ✓ | |||
| L1CAM | SPG11 | ✓ | ✓ | L1 syndrome | |||
| MAG* | SPG75 | ✓ | ✓ | ||||
| NIPA1 | SPG6 | ✓ | ✓ | ✓ | |||
| NT5C2 | SPG45 | ✓ | ✓ | ||||
| PGAP1* | ✓ | ✓ | intellectual disability | ||||
| PLP1 | SPG2 | ✓ | ✓ | Pelizaeus-Merzbacher disease | |||
| PNPLA6 | SPG39 | ✓ | ✓ | Boucher-Neuhäuser syndrome, Oliver-McFarlane/Laurence-Moon syndrome | |||
| RAB3GAP2* | ✓ | ✓ | Warburg Micro syndrome-2, Martsolf syndrome | ||||
| REEP1 | SPG31 | ✓ | ✓ | ✓ | distal hereditary motor neuropathy | ||
| REEP2 | SPG72 | ✓ | ✓ | ✓ | |||
| RTN2 | SPG12 | ✓ | ✓ | ||||
| SACS | ARSACS | ✓ | ✓ | autosomal recessive spastic ataxia of Charlevoix-Saguenay | |||
| SLC16A2 | ✓ | ✓ | MCT8-specific thyroid hormone cell transporter deficiency (Allan-Herndon-Dudley syndrome) | ||||
| SLC33A1* | SPG42 | ✓ | ✓ | congenital cataracts, hearing loss, and neurodegeneration | |||
| SPART (formerly known as SPG20) | SPG20 | ✓ | ✓ | Troyer syndrome | |||
| SPAST | SPG4 | ✓ | ✓ | ✓ | |||
| SPG7 | SPG7 | ✓ | ✓ | ✓ | primary lateral sclerosis | ||
| SPG11 | SPG11 | ✓ | ✓ | Charcot-Marie-Tooth disease, type-2; amyotrophic lateral sclerosis | |||
| SPG21 | SPG21 | ✓ | ✓ | ||||
| TECPR2 | SPG49 | ✓ | ✓ | ||||
| TFG* | SPF57 | ✓ | ✓ | hereditary motor and sensory neuropathy, Okinawa type | |||
| USP8* | ✓ | ✓ | |||||
| VAMP1 | SPAX1 | ✓ | ✓ | ||||
| VPS37A* | SPG53 | ✓ | ✓ | ||||
| WASHC5 (formerly known as KIAA0196) | SPG8 | ✓ | ✓ | Ritscher-Schinzel syndrome 1 | |||
| ZFR* | SPG71 | ✓ | ✓ | ||||
| ZFYVE26 | SPG15 | ✓ | ✓ | Kjellin syndrome | |||
| ZFYVE27* | SPG33 | ✓ | ✓ | ||||
*Preliminary-evidence gene
Clinical sensitivity
This multi-gene panel analyzes up to 65 genes, including the most common genetic causes of HSP: ATL1, CYP7B1, K1F5A, REEP1, SPAST, SPG11, and SPG7. Other rare genes are also included on this panel, which increases the clinical sensitivity of this test, though the exact contribution of these additional genes to HSP is not known. In previous studies, the percent of families who received a genetic diagnosis after systematic testing ranged from 33% to 55% in autosomal dominant HSP and 18% to 29% in autosomal recessive HSP.
Inheritance
HSP can be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern.
Penetrance
The penetrance of HSP varies depending on the causative gene and the specific pathogenic variant. Certain genes, such as HSPD1, REEP1, and SPAST, are known to have reduced penetrance and variable expression within a family. Average age of onset also varies by gene and can occur at any time from early childhood to age 70.
Prevalence/Incidence
The prevalence of HSP has been estimated at 1 in 10,000 to 1 in 100,000 people. Approximately 90% of these cases are uncomplicated and 10% present as complicated HSP.
Considerations for testing
The clinical presentation of HSP can be variable. Genetic testing may confirm a suspected diagnosis or rule out disorders with similar symptoms. A genetic diagnosis may also help predict disease progression or inform family planning.
References
- Beetz, C, et al. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain. 2008; 131(Pt 4):1078-86. doi: 10.1093/brain/awn026. PMID: 18321925
- Depienne, C, et al. Hereditary spastic paraplegias: an update. Curr. Opin. Neurol. 2007; 20(6):674-80. doi: 10.1097/WCO.0b013e3282f190ba. PMID: 17992088
- Faber, I, et al. Clinical features and management of hereditary spastic paraplegia. Arq Neuropsiquiatr. 2014; 72(3):219-26. doi: (10.1055/s-0034-1386767). PMID: 24676440
- Fink, JK. Hereditary spastic paraplegia. Curr Neurol Neurosci Rep. 2006; 6(1):65-76. doi: 10.1007/3-540-29623-9_1330. PMID: 23897027
- Fink, JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol. 2013; 126(3):307-28. doi: 10.1007/s00401-013-1115-8. PMID: 16469273
- Finsterer, J, et al. Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. J. Neurol. Sci. 2012; 318(1-2):1-18. doi: 10.1016/j.jns.2012.03.025. PMID: 22554690
- Noreau, A, et al. Molecular aspects of hereditary spastic paraplegia. Exp. Cell Res. 2014; 325(1):18-26. PMID: 24631291
- Ruano, L, et al. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014; 42(3):174-83. PMID: 24603320
Assay
Assay and technical information
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
| Gene | Transcript reference | Sequencing analysis | Deletion/Duplication analysis |
|---|---|---|---|
| ABCD1 | NM_000033.3 | ||
| ALDH18A1 | NM_002860.3 | ||
| ALS2 | NM_020919.3 | ||
| AMPD2 | NM_001257360.1 | ||
| AP4B1 | NM_006594.3 | ||
| AP4E1 | NM_007347.4 | ||
| AP4M1 | NM_004722.3 | ||
| AP4S1 | NM_007077.4 | ||
| AP5Z1 | NM_014855.2 | ||
| ARL6IP1 | NM_015161.1 | ||
| ARSI | NM_001012301.2 | ||
| ATL1 | NM_015915.4 | ||
| ATP13A2 | NM_022089.3 | ||
| B4GALNT1 | NM_001478.4 | ||
| BSCL2 | NM_032667.6 | ||
| C12orf65 | NM_152269.4 | ||
| C19orf12 | NM_001031726.3 | ||
| CCT5 | NM_012073.3 | ||
| CPT1C | NM_001136052.2 | ||
| CYP2U1 | NM_183075.2 | ||
| CYP7B1 | NM_004820.3 | ||
| DDHD1 | NM_001160147.1 | ||
| DDHD2 | NM_015214.2 | ||
| ENTPD1 | NM_001776.5 | ||
| ERLIN1 | NM_006459.3 | ||
| ERLIN2 | NM_007175.6 | ||
| EXOSC3 | NM_016042.3 | ||
| FA2H | NM_024306.4 | ||
| GBA2 | NM_020944.2 | ||
| GJC2* | NM_020435.3 | ||
| HEXA | NM_000520.4 | ||
| HSPD1 | NM_002156.4 | ||
| IBA57 | NM_001010867.3 | ||
| KDM5C | NM_004187.3 | ||
| KIF1A | NM_004321.6 | ||
| KIF1C | NM_006612.5 | ||
| KIF5A | NM_004984.2 | ||
| L1CAM | NM_000425.4 | ||
| MAG | NM_002361.3 | ||
| NIPA1 | NM_144599.4 | ||
| NT5C2 | NM_012229.4 | ||
| PGAP1 | NM_024989.3 | ||
| PLP1 | NM_000533.4 | ||
| PNPLA6 | NM_006702.4 | ||
| RAB3GAP2 | NM_012414.3 | ||
| REEP1 | NM_022912.2 | ||
| REEP2 | NM_001271803.1 | ||
| RTN2 | NM_005619.4 | ||
| SACS | NM_014363.5 | ||
| SLC16A2 | NM_006517.4 | ||
| SLC33A1 | NM_004733.3 | ||
| SPART | NM_015087.4 | ||
| SPAST | NM_014946.3 | ||
| SPG11 | NM_025137.3 | ||
| SPG21 | NM_016630.6 | ||
| SPG7 | NM_003119.3 | ||
| TECPR2 | NM_014844.3 | ||
| TFG | NM_006070.5 | ||
| USP8 | NM_005154.4 | ||
| VAMP1 | NM_014231.3 | ||
| VPS37A | NM_152415.2 | ||
| WASHC5 | NM_014846.3 | ||
| ZFR | NM_016107.3 | ||
| ZFYVE26 | NM_015346.3 | ||
| ZFYVE27 | NM_001002261.3 |
GJC2: Analysis includes the promoter variants NM_020435.3:c.-167A>G and NM_020435.3:c.-170A>G.
Resources
Patient resources
Patient guide: Genetic testing simplifiedReferences
- Beetz, C, et al. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain. 2008; 131(Pt 4):1078-86. doi: 10.1093/brain/awn026. PMID: 18321925
- Depienne, C, et al. Hereditary spastic paraplegias: an update. Curr. Opin. Neurol. 2007; 20(6):674-80. doi: 10.1097/WCO.0b013e3282f190ba. PMID: 17992088
- Faber, I, et al. Clinical features and management of hereditary spastic paraplegia. Arq Neuropsiquiatr. 2014; 72(3):219-26. doi: (10.1055/s-0034-1386767). PMID: 24676440
- Fink, JK. Hereditary spastic paraplegia. Curr Neurol Neurosci Rep. 2006; 6(1):65-76. doi: 10.1007/3-540-29623-9_1330. PMID: 23897027
- Fink, JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol. 2013; 126(3):307-28. doi: 10.1007/s00401-013-1115-8. PMID: 16469273
- Finsterer, J, et al. Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. J. Neurol. Sci. 2012; 318(1-2):1-18. doi: 10.1016/j.jns.2012.03.025. PMID: 22554690
- Noreau, A, et al. Molecular aspects of hereditary spastic paraplegia. Exp. Cell Res. 2014; 325(1):18-26. PMID: 24631291
- Ruano, L, et al. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014; 42(3):174-83. PMID: 24603320
