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  • Test code: 03262
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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  1. Neurology
  2. Invitae Hereditary Spastic Paraplegia Autosomal Recessive Panel

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.

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Primary panel (30 genes)

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

Panel details and technical assay limitations
Add-on Preliminary-evidence Genes for Hereditary Spastic Paraplegia Autosomal Recessive (17 genes)

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

Panel details and technical assay limitations

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

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.









GeneSubtypeInheritanceClinical formAssociated syndromes and other related disorders
Autosomal dominantAutosomal recessiveX-linkedUncomplicatedComplicated
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

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.

This test is specific for subtypes of HSP that are inherited in an autosomal recessive pattern.

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.

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.

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.

  1. 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
  2. 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
  3. Noreau, A, et al. Molecular aspects of hereditary spastic paraplegia. Exp. Cell Res. 2014; 325(1):18-26. PMID: 24631291
  4. 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
  5. 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
  6. Fink, JK. Hereditary spastic paraplegia. Curr Neurol Neurosci Rep. 2006; 6(1):65-76. doi: 10.1007/3-540-29623-9_1330. PMID: 23897027
  7. Depienne, C, et al. Hereditary spastic paraplegias: an update. Curr. Opin. Neurol. 2007; 20(6):674-80. doi: 10.1097/WCO.0b013e3282f190ba. PMID: 17992088

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

Clinical resources
Invitae brochure Neurology gene list
Patient resources
Patient guide: Genetic testing simplified
Test information
Forms page Specimen requirements page

References

  1. Depienne, C, et al. Hereditary spastic paraplegias: an update. Curr. Opin. Neurol. 2007; 20(6):674-80. doi: 10.1097/WCO.0b013e3282f190ba. PMID: 17992088
  2. 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
  3. Fink, JK. Hereditary spastic paraplegia. Curr Neurol Neurosci Rep. 2006; 6(1):65-76. doi: 10.1007/3-540-29623-9_1330. PMID: 23897027
  4. 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
  5. 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
  6. Noreau, A, et al. Molecular aspects of hereditary spastic paraplegia. Exp. Cell Res. 2014; 325(1):18-26. PMID: 24631291
  7. 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

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