Invitae Hereditary Spastic Paraplegia Autosomal Recessive Panel
Test description
The Invitae Hereditary Spastic Paraplegia Autosomal Recessive Panel analyzes up to 47 genes that cause hereditary spastic paraplegia (HSP) that is inherited in an autosomal recessive pattern. These genes include the most common causes of autosomal recessive HSP—specifically, CYP7B1, SPG7, and SPG11.
Genes tested
Primary panel
ALDH18A1 ALS2 AP4B1 AP4E1 AP4M1 AP4S1 AP5Z1 B4GALNT1 C12orf65 CYP2U1 CYP7B1 DDHD1 DDHD2 ERLIN2 FA2H GBA2 GJC2 HEXA KIF1A KIF1C NT5C2 PNPLA6 REEP2 SACS SPART SPG11 SPG21 SPG7 TECPR2 ZFYVE26
Add-on Preliminary-evidence Genes for Hereditary Spastic Paraplegia Autosomal Recessive
AMPD2 ARL6IP1 ARSI ATP13A2 C19orf12 CCT5 ENTPD1 ERLIN1 EXOSC3 IBA57 MAG PGAP1 RAB3GAP2 TFG USP8 VPS37A ZFR
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 (30 genes)
Customized gene selection (0 included, 0 excluded)
ALDH18A1 ALS2 AP4B1 AP4E1 AP4M1 AP4S1 AP5Z1 B4GALNT1 C12orf65 CYP2U1 CYP7B1 DDHD1 DDHD2 ERLIN2 FA2H GBA2 GJC2 HEXA KIF1A KIF1C NT5C2 PNPLA6 REEP2 SACS SPART SPG11 SPG21 SPG7 TECPR2 ZFYVE26
Add-on Preliminary-evidence Genes for Hereditary Spastic Paraplegia Autosomal Recessive (17 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 ENTPD1 ERLIN1 EXOSC3 IBA57 MAG PGAP1 RAB3GAP2 TFG USP8 VPS37A ZFR
Alternative tests to consider
For a broader analysis, clinicians may consider the Invitae Hereditary Spastic Paraplegia Comprehensive panel. It includes genes with dominant, recessive, and X-linked inheritance and is particularly helpful if the inheritance is unclear. This broader panel can be ordered at no additional charge.
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.
| Gene | Subtype | Inheritance | Clinical form | Associated syndromes and other related disorders | |||
|---|---|---|---|---|---|---|---|
| Autosomal dominant | Autosomal recessive | X-linked | Uncomplicated | Complicated | |||
| 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* | ✓ | ✓ | |||||
| ATP13A2* | SPG78 | ✓ | ✓ | Kufor-Rakeb syndrome | |||
| B4GALNT1 | SPG26 | ✓ | ✓ | ||||
| C12ORF65 | SPG55 | ✓ | ✓ | ||||
| C19ORF12* | SPG43 | ✓ | ✓ | neurodegeneration with brain iron accumulation type 4 | |||
| CCT5* | ✓ | ✓ | hereditary sensory neuropathy with spastic paraplegia | ||||
| CYP2U1 | SPG56 | ✓ | ✓ | ||||
| CYP7B1 | SPG5 | ✓ | ✓ | ✓ | |||
| DDHD1 | SPG28 | ✓ | ✓ | ✓ | |||
| DDHD2 | SPG54 | ✓ | ✓ | ||||
| ENTPD1* | SPG64 | ✓ | ✓ | ||||
| ERLIN1* | SPG62 | ✓ | ✓ | ||||
| ERLIN2 | SPG18 | ✓ | ✓ | ||||
| EXOSC3* | ✓ | ✓ | pontocerebellar hypoplasia, type 1B | ||||
| FA2H | SPG35 | ✓ | ✓ | ||||
| GBA2 | SPG46 | ✓ | ✓ | ||||
| GJC2 | SPG44 | ✓ | ✓ | hypomyelinating leukodystrophy; hereditary lymphedema | |||
| HEXA | ✓ | ✓ | Hexosaminidase A deficiency | ||||
| IBA57* | SPG74 | ✓ | ✓ | ||||
| KIF1A | SPG30 | ✓ | ✓ | ✓ | |||
| KIF1C | SPAX2 | ✓ | ✓ | spastic ataxia 2 | |||
| MAG* | SPG75 | ✓ | ✓ | ||||
| NT5C2 | SPG45 | ✓ | ✓ | ||||
| PGAP1* | ✓ | ✓ | intellectual disability | ||||
| PNPLA6 | SPG39 | ✓ | ✓ | Boucher-Neuhäuser syndrome, Oliver-McFarlane/Laurence-Moon syndrome | |||
| RAB3GAP2* | ✓ | ✓ | Warburg Micro syndrome-2, Martsolf syndrome | ||||
| REEP2 | SPG72 | ✓ | ✓ | ✓ | |||
| SACS | ARSACS | ✓ | ✓ | autosomal recessive spastic ataxia of Charlevoix-Saguenay | |||
| SPART (formerly known as SPG20) | SPG20 | ✓ | ✓ | Troyer syndrome | |||
| 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* | ✓ | ✓ | |||||
| VPS37A* | SPG53 | ✓ | ✓ | ||||
| ZFR* | ✓ | ✓ | |||||
| ZFYVE26 | SPG15 | ✓ | ✓ | Kjellin syndrome | |||
*Preliminary-evidence gene
Clinical sensitivity
This multi-gene panel analyzes up to 47 genes, including the most common genetic causes of autosomal recessive HSP, SPG11 and CYP7B1. 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 18% to 29% for autosomal recessive HSP.
Inheritance
This test is specific for subtypes of HSP that are inherited in an autosomal recessive pattern.
Penetrance
The penetrance of HSP varies depending on the causative gene and the specific pathogenic variant. Onset of HSP symptoms can occur at any time from early childhood to age 70. Onset of SPG5 and SPG11 typically occurs in childhood through early adulthood, while onset of SPG7 typically occurs later in adulthood.
Prevalence/Incidence
The overall prevalence of HSP has been estimated at 1 in 10,000 to 1 in 100,000 people, but a minority of cases are inherited in an autosomal recessive pattern.
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 or carrier screening.
References
- Depienne, C, et al. Hereditary spastic paraplegias: an update. Curr. Opin. Neurol. 2007; 20(6):674-80. doi: 10.1097/WCO.0b013e3282f190ba. PMID: 17992088
- 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
- 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
- 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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
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 |
|---|---|---|---|
| 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 | ||
| ATP13A2 | NM_022089.3 | ||
| B4GALNT1 | NM_001478.4 | ||
| C12orf65 | NM_152269.4 | ||
| C19orf12 | NM_001031726.3 | ||
| CCT5 | NM_012073.3 | ||
| 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 | ||
| IBA57 | NM_001010867.3 | ||
| KIF1A | NM_004321.6 | ||
| KIF1C | NM_006612.5 | ||
| MAG | NM_002361.3 | ||
| NT5C2 | NM_012229.4 | ||
| PGAP1 | NM_024989.3 | ||
| PNPLA6 | NM_006702.4 | ||
| RAB3GAP2 | NM_012414.3 | ||
| REEP2 | NM_001271803.1 | ||
| SACS | NM_014363.5 | ||
| SPART | NM_015087.4 | ||
| SPG11 | NM_025137.3 | ||
| SPG21 | NM_016630.6 | ||
| SPG7 | NM_003119.3 | ||
| TECPR2 | NM_014844.3 | ||
| TFG | NM_006070.5 | ||
| USP8 | NM_005154.4 | ||
| VPS37A | NM_152415.2 | ||
| ZFR | NM_016107.3 | ||
| ZFYVE26 | NM_015346.3 |
Resources
Patient resources
Patient guide: Genetic testing simplifiedReferences
- 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
