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Holocarboxylase Synthetase Deficiency via the HLCS Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9651 HLCS 81406 81406,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9651HLCS81406 81406(x1), 81479(x1) $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

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

Multiple carboxylase deficiency (MCD) is an inborn error of metabolism resulting from defective biotin metabolism. Early-onset MCD (OMIM #253270) results from deficiency of holocarboxylase synthetase (HLCS), whereas juvenile (also called late)-onset MCD (OMIM #253260) is caused by biotinidase (BTD) deficiency. BTD and HLCS forms of MCD are both responsive to biotin therapy. However, making a distinction between the two types is difficult and relies largely on age of onset rather than clinical features. Clinical signs of juvenile-onset BTD typically appear after 3 months of age while early-onset MCD is typically evident earlier than 3 months of age (Wolf et al. Ann Neurol 18:614-617, 1985). In vitro enzyme studies are capable of distinguishing between the two disorders. The earliest presenting sign is usually seizures, but other early, non-specific symptoms include hypotonia, respiratory symptoms, developmental delay, and ataxia. Eczema, alopecia, dermatitis, and skin infections are also common findings, and cutaneous presentations in conjunction with neurological symptoms greatly limit the differential diagnosis. Clinical variability for HLCS-related MCD is documented, and an asymptomatic homozygous adult has been reported (Suzuki et al. Hum Mutat 26:285-290, 2005).

Genetics

HLCS-related multiple carboxylase deficiency (MCD) is an autosomal recessive disorder. Variants in the HLCS gene are the genetic cause of early-onset MCD. Approximately 30 HLCS variants have been reported. Most variants are missense changes but nonsense variants, small insertions and deletions, gross deletions, and splice site variants have also been found. Among Northern Europeans a splice site variant (c.1519+5G>A) is prevalent, and among Japanese patients two variants (p.Leu237Pro and p.Gly261Valfs*20) are predominant (Suzuki et al. Hum Mutat 26:285-290, 2005). The p.Arg508Trp variant has been found in multiple patients from several ethnic groups in East Asia, the Middle East, and the USA (Suzuki et al. Hum Mutat 26:285-290, 2005).

Clinical Sensitivity - Sequencing with CNV PGxome

Dupuis et al. (Hum Molec Genet 5:1011-1016, 1996) found two causative HLCS variants in each of nine patients studied, and Aoki et al. (Hum Genet 104:143-148, 1999) found two causative variants in each of their seven holocarboxylase synthetase deficient patients.

Testing Strategy

This test provides full coverage of all coding exons of the HLCS 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Patients suspected of having multiple carboxylase deficiency based on biochemical testing or clinical features. All patients with reduced holocarboxylase synthetase activity are candidates for this test. We will also sequence the HLCS gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
HLCS 609018
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Multiple Carboxylase Defiency, Early Onset AR 253270

Citations

  • Aoki, Y., et.al. (1999). "Identification and characterization of mutations in patients with holocarboxylase synthetase deficiency." Hum Genet 104(2): 143-8. PubMed ID: 10190325
  • Dupuis, L., et.al. (1996). "Clustering of mutations in the biotin-binding region of holocarboxylase synthetase in biotin-responsive multiple carboxylase deficiency." Hum Mol Genet 5(7): 1011-6. PubMed ID: 8817339
  • Suzuki, Y., et.al. (2005). "Mutations in the holocarboxylase synthetase gene HLCS." Hum Mutat 26(4): 285-90. PubMed ID: 16134170
  • Wolf, B., et.al. (1985). "Biotinidase deficiency: initial clinical features and rapid diagnosis." Ann Neurol 18(5): 614-7. PubMed ID: 4073853

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

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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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.
Total Price: $
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