DNA icon

Spastic Paraplegia and Psychomotor Retardation with or without Seizures (SPPRS) via the HACE1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
HACE1 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15243HACE181479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Greg Fischer, PhD

Clinical Features and Genetics

Clinical Features

Hereditary spastic paraplegia (HSP) is a group of clinically and genetically diverse diseases, characterized by spasticity (rigid muscles) and lower extremity weakness (Fink. 2014. PubMed ID: 25192507; Hensiek et al. 2015. PubMed ID: 25480570). Historically, some HSPs are classified as “complex” if the impairments in the lower limb are also accompanied by other systemic or neurologic abnormalities such as seizures, ataxia, intellectual disability, dementia, and vision and hearing impairment (Hedera. 2018. PubMed ID: 20301682).

Pathogenic variants in HACE1 have been implicated as a monogenic cause of SPPRS (spastic-paraplegia-psychomotor-retardation -seizures syndrome, or spastic paraplegia and psychomotor retardation with or without seizures), a rare type of complex HSP with onset in infancy. SPPRS affects diverse ethnic groups, with a prevalence estimated at less than 1 in 1,000,000. Most patients present as newborns with muscular hypotonia followed by global developmental delay, intellectual disability, progressive lower limb spasticity, and often seizures. Minor features of SPPRS are highly variable, and may include ocular abnormalities such as strabismus and/or retinal dystrophy, cerebral atrophy, and hypoplasia of the corpus callosum (Hollstein et al. 2015. PubMed ID: 26424145)

While there are currently no treatments reported for SPPRS, patients and their families may benefit from a molecular diagnosis for prognostic information, symptom management, and reproductive planning.


The majority of variants in HACE1 reported as causative for SPPRS are biallelic truncating loss-of-function variants in a compound heterozygous or homozygous state, consistent with autosomal recessive inheritance (Akawi et al. 2015. PubMed ID: 26437029; Hollstein et al. 2015. PubMed ID: 26424145; Nagy et al. 2019. PubMed ID: 31321300).

HACE1 encodes HECT Domain and Ankyrin Repeat Containing E3 Ubiquitin Protein Ligase 1 (HACE1), an E3 ubiquitin ligase that catalyzes the covalent attachment of ubiquitin moieties to cellular GTPases to target them for degradation by the proteasome, thus antagonizing cellular GTPase activity to regulate a variety of cellular processes (Tang et al. 2011. PubMed ID: 21988917; Torrino et al. 2011. PubMed ID: 22036506).

HACE1 has two known functional domains: the ankyrin repeat region responsible for substrate recognition proximal to the N-terminus (AA 64-257) and the catalytic HECT domain critical for ubiquitin conjugation at the very C-terminus (AA 572-909). Most pathogenic HACE1 variants reported in patients with SPPRS are predicted to result in nonsense-mediated mRNA decay or a truncated protein product with no catalytic activity (Nagy et al. 2019. PubMed ID: 31321300). A homozygous variant predicted to result in the in-frame deletion of a highly conserved residue within the catalytic HECT domain has also been reported in patients with SPPRS (Akawi et al. 2015. PubMed ID: 26437029), suggesting that loss of HACE1 catalytic activity rather than loss of HACE1 protein is important for development of SPPRS.

Heterozygous de novo missense variants in the molecular pathway downstream of HACE1 in RAC1 (encodes a substrate of HACE1) and TRIO (Rac1-GEF) are reported to result in clinical manifestations that overlap with SPPRS, including hypotonia, global developmental delay, and intellectual disability (Reijnders et al. 2017. PubMed ID: 28886345). However, these patients do not exhibit progressive spasticity, a hallmark feature of SPPRS. Thus, HACE1-deficiency appears to be the major cause of SPPRS.

Primary neonatal cardiomyocytes and embryonic fibroblasts derived from homozygous Hace1 knock-out mice are viable in cell culture (Zhang et al. 2014. PubMed ID: 24614889), suggesting HACE1 is not an essential gene for cell survival. Importantly, homozygous Hace1 knock-out mice exhibit brain morphologies and phenotypes similar to patients with SPPRS, including hypoplasia of the corpus callosum, as well as movement and learning deficiencies (Nagy et al. 2019. PubMed ID: 31321300).

Clinical Sensitivity - Sequencing with CNV PG-Select

Clinical sensitivity is difficult to estimate because only a small number of patients with SPPRS have been reported. Due to phenotypic heterogeneity and rarity of SPPRS, as well as phenotypic overlap with other complex HSPs, clinical sensitivity may be low. Analytical sensitivity should be high because all pathogenic variants reported to date are detectable by sequencing.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the HACE1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

This test is suitable for patients presenting with infancy-onset hypotonia followed by global developmental delay and intellectual disability, progressive lower limb spasticity, and possibly seizures. Due to high clinical and genetic heterogeneity of both complex HSPs and intellectual disability, HACE1 could be included as part of a larger sequencing panel or exome test. We will sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known pathogenic variants or to confirm research results. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in HACE1.


Official Gene Symbol OMIM ID
HACE1 610876
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT



Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

loading Loading... ×


An error has occurred while calculating the price. Please try again or contact us for assistance.

View Ordering Instructions

1) Select Test Method (Platform)

1) Select Test Type

2) Select Additional Test Options

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: loading
Patient Prompt Pay Price: loading
A patient prompt pay discount is available if payment is made by the patient and received prior to the time of reporting.
Show Patient Prompt Pay Price
Copy Text to Clipboard