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  • Test code: 03251
  • 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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Invitae Hereditary Spastic Paraplegia Comprehensive Panel

Test description

The Invitae Hereditary Spastic Paraplegia Comprehensive Panel analyzes up to 64 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.

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Primary panel (43 genes)

ABCD1 ALDH18A1 ALS2 AP4B1 AP4E1 AP4M1 AP4S1 AP5Z1 ATL1 B4GALNT1 BSCL2 C12orf65 CYP2U1 CYP7B1 DDHD1 DDHD2 ERLIN2 FA2H GBA2 GJC2 HSPD1 KDM5C KIF1A KIF1C KIF5A L1CAM NIPA1 NT5C2 PLP1 PNPLA6 REEP1 RTN2 SACS SLC16A2 SPAST SPG11 SPG20 SPG21 SPG7 TECPR2 VAMP1 WASHC5 ZFYVE26

Add-on Preliminary-evidence Genes for Hereditary Spastic Paraplegia (21 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 CPT1C ENTPD1 ERLIN1 EXOSC3 IBA57 MAG PGAP1 RAB3GAP2 REEP2 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.

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.

GeneSubtypeInheritanceClinical formAssociated syndromes and other related disorders
Autosomal dominantAutosomal recessiveX-linkedUncomplicatedComplicated
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
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
SPAST SPG4
SPG7 SPG7 primary lateral sclerosis
SPG11 SPG11 Charcot-Marie-Tooth disease, type-2; amyotrophic lateral sclerosis
SPG20 SPG20 Troyer syndrome
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

This multi-gene panel analyzes up to 64 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.

HSP can be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern.

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.

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.

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.

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

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; NM_001122955.3
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
HSPD1 NM_002156.4
IBA57 NM_001010867.3
KDM5C NM_004187.3
KIF1A NM_004321.6; NM_001244008.1
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
SPAST NM_014946.3
SPG11 NM_025137.3
SPG20 NM_015087.4
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.