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Creatine Deficiency Syndrome via the SLC6A8 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
7831 SLC6A8 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7831SLC6A881479 81479,81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

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

Turnaround Time

18 days on average for standard orders or 13 days 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

Creatine transporter (CrT) deficiency is an inborn error of creatine biosynthesis causing cerebral creatine deficiency syndrome (CCDS), which typically has an onset in childhood. The creatine transporter protein is required to move creatine out of the blood and into cells, as well as between different cells following endogenous creatine synthesis (Cheillan and Sedel 2016). Characteristic biochemical findings of CrT deficiency include normal levels of creatine and guanidinoacetate (GAA) in the plasma and urine and a normal GAA/creatinine ratio in the plasma. A finding considered pathognomic for CrT deficiency is a high creatine/creatinine ratio in the urine, although it should be noted that this can be normal in affected females (Mercimek-Mahmutoglu and Salomons 2015; Ardon et al. 2016; Cheillan and Sedel 2016). Direct measurement of total creatine levels in the brain is possible by in vivo proton magnetic resonance spectroscopy (1H-MRS) (Stromberger et al. 2003). In CrT deficient patients, 1H-MRS analysis reveals a complete absence or dramatic decrease in the brain creatine peak (Heussinger et al. 2017).

All patients with CrT deficiency present with non-progressive intellectual disability (ID) that can range from mild to severe and is associated with language delays (Cheillan and Sedel 2016). In addition to these patients with non-syndromic ID, other patients present with syndromic ID. Additional findings in the syndromic patients can include seizures, movement disorders, behavior disorders, hypotonia and spasticity, dysmorphic features, gastrointestinal findings, and rarely, cardiac findings (Mercimek-Mahmutoglu and Salomons 2015; Cheillan and Sedel 2016). Treatment of CrT deficient patient with dietary methods has thus far had limited success (Fons et al. 2008). However, clinical trials for pharmaceutical therapy are underway (https://clinicaltrials.gov).

It should be noted that secondary creatine deficiency can be caused by defects in the urea and remethylation cycles as well as by ornithine aminotransferase deficiency (Cheillan and Sedel 2016). If creatine deficiency is suspected based on biochemical tests, but primary cerebral creatine deficiency syndromes are ruled out via genetic and enzyme testing, consideration should be given to these disorders.

Genetics

CrT deficiency is inherited in an X-linked recessive fashion. The majority of reported patients are male, though affected females have also been reported. Females carrying pathogenic SLC6A8 variants range from asymptomatic to severely affected (Mercimek-Mahmutoglu and Salomons 2015). Approximately 30% of pathogenic variants have been reported to occur de novo, while the rest are maternally inherited (Mercimek-Mahmutoglu and Salomons 2015). To date, over 100 pathogenic variants have been reported in the SLC6A8 gene. The most common types of variants reported are missense and small deletions, though nonsense, splicing, and small insertions and indels have been reported, as well as gross deletions and duplications (Human Gene Mutation Database). No obvious genotype-phenotype correlations have yet been made (Mercimek-Mahmutoglu and Salomons 2015). The most commonly reported pathogenic variants are p.Phe107del, p.Pro544Leu and p.Pro554Leu (van de Kamp et al. 2013; Mercimek-Mahmutoglu and Salomons 2015; SLC6A8 Variant Database).

Creatine is required for the storage and transmission of high energy phosphates (such as ATP) in the muscle and brain (Cheillan and Sedel 2016). Endogenous creatine synthesis occurs via the action of the L-arginine:glycine amidinotransferase (AGAT) and N-guanidinoacetate methyltransferase (GAMT) enzymes. The SLC6A8 gene encodes the creatine transporter protein which is required for the uptake of creatine from the blood into cells. In addition, the creatine transporter is required for the transport of guanidinoacetate (GAA) between cells in organs that do not express both AGAT and GAMT in the same cells. This is particularly true in the brain, and explains why deficiencies in the AGAT, GAMT and SLC6A8 proteins result in a large cerebral creatine deficit (Cheillan and Sedel 2016).

Clinical Sensitivity - Sequencing with CNV PG-Select

In cohorts of patients with X-linked intellectual disability (XLID), pathogenic variants in SLC6A8 have been reported to account for ~0.6 - 3.3% of cases. In cohorts of patients with generalized intellectual disability (syndromic or non-syndromic ID), pathogenic variants in SLC6A8 have been reported to account for ~1.4% of cases (Mercimek-Mahmutoglu and Salomons 2015).

In one study of patients suspected of a cerebral creatine deficiency syndrome (CCDS) based on clinical features, 26 pathogenic variants were identified in 195 patients, for a sensitivity of ~13.3% (Comeaux et al. 2013). In a retrospective study of 101 male patients with clinical, biochemical, enzymatic and neuroimaging test results consistent with creatine transporter deficiency, all patients carried a pathogenic variant in SLC6A8. In ~96% of these patients, the variant was a small variant detectable via direct sequencing, while the remaining ~4% were found to carry gross deletions (van de Kamp et al. 2013).

Testing Strategy

This test provides full coverage of all coding exons of the SLC6A8 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

This test also includes coverage for the intronic variants c.1392+24_1393_30del and c.1016+21_1016+54del (Hathaway et al. 2010; Cervera-Acedo et al. 2015).

Indications for Test

Patients with biochemical test results (especially a high creatine/creatinine ratio in the urine), impaired creatine uptake in cultured fibroblasts, and/or an absent or greatly decreased brain creatine peak by 1H-MRS analysis are good candidates for this test, particularly if X-linked inheritance is suspected. In addition, young children with global developmental delay, hypotonia, seizures and a movement disorder or older children with intellectual disability with speech delay, epilepsy, a movement disorder and behavior problems are also good candidates for this test. Testing is also indicated for maternal family members of patients with known SLC6A8 pathogenic variants, and we will also sequence the SLC6A8 gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
SLC6A8 300036
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Cerebral Creatine Deficiency Syndrome 1 XL 300352

Citations

  • Ardon O. et al. 2016. Molecular Genetics and Metabolism Reports. 8: 20-3. PubMed ID: 27408820
  • Cervera-Acedo C. et al. 2015. Human Genome Variation. 2: 15037. PubMed ID: 27081545
  • Cheillan D. and Sedel F. 2016. Disorders of Creatine Metabolism. In: Hollak C.E.M. and Lachmann R.H., editors. Inherited Metabolic Disease in Adults: A Clinical Guide. New York: Oxford University Press, p 541-551.
  • ClinicalTrials.gov (https://clinicaltrials.gov)
  • Comeaux M.S. et al. 2013. Molecular Genetics and Metabolism. 109: 260-8. PubMed ID: 23660394
  • Fons C. et al. 2008. Journal of Inherited Metabolic Disease. 31: 724-8. PubMed ID: 18925426
  • Hathaway S.C. et al. 2010. Journal of Child Neurology. 25: 1009-12. PubMed ID: 20501887
  • Heussinger N. et al. 2017. Pediatric Neurology. 67: 45-52. PubMed ID: 28065824
  • Human Gene Mutation Database (Bio-base).
  • Mercimek-Mahmutoglu S. and Salomons G.S. 2015. Creatine Deficiency Syndromes. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301745
  • SLC6A8 Variant Database: http://grenada.lumc.nl/LOVD2/vumc/home.php?select_db=SLC6A8
  • Stromberger C. et al. 2003. Journal of Inherited Metabolic Disease. 26: 299-308. PubMed ID: 12889668
  • van de Kamp J.M. et al. 2013. Journal of Medical Genetics. 50: 463-72. PubMed ID: 23644449

Ordering/Specimens

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


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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