Congenital Central Hypoventilation Syndrome (CCHS) Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10239 ASCL1 81479,81479 Order Options and Pricing
BDNF 81479,81479
BMP2 81479,81479
EDN3 81479,81479
PHOX2A 81479,81479
PHOX2B 81404,81403
RET 81406,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10239Genes x (7)81479 81403, 81404, 81406, 81479 $990 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

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

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

Clinical Features and Genetics

Clinical Features

Congenital Central Hypoventilation Syndrome (CCHS) is a rare disorder that affects breathing (alveolar hypoventilation) and autonomic regulation. It often occurs in newborns and less frequently as a milder condition in young children and adults. Individuals affected with CCHS require assistance for breathing via a ventilator 24 hours a day or only during sleep. Tracheostomy along with assisted ventilation is especially recommended for young children (Weese-Mayer et al. 2014). Some individuals with CCHS also have associated Hirschsprung disease (HSCR) and/or neuroblastomas in up to 20% and 6% of cases, respectively. CCHS is also known as Ondine's curse and Haddad syndrome; the latter refers to the co-occurrence of CCHS and HSCR (Lai and Schroer 2008), but neither term is commonly used. The prevalence of CCHS is estimated at 1,000 individuals worldwide, but this may be an underestimate because individuals with a milder phenotype are underdiagnosed (Weese-Mayer et al. 2010).

Genetics

Congenital Central Hypoventilation Syndrome is inherited in an autosomal dominant manner and mainly caused by PHOX2B mutations. PHOX2B encodes a transcription factor that is involved in the normal sympathetic neuronal development and catecholamine synthesis. Two major types of mutations occur in PHOX2B. These are heterozygous polyalanine repeat expansion mutations (PARMs) and non-polyalanine repeat expansion mutations (NPARMs). An unaffected individual generally is homozygous for 20 alanine repeats. Less than 20 repeats have also been reported and are generally considered benign, although the repeat numbers have not been extensively studied with respect to breathing deficit or autonomic dysregulation (Weese-Mayer et al. 2014). Individuals who are heterozygous for reported 24-33 alanine repeats are affected with CCHS, with increasing allele size correlating with increasing disease severity and earlier age of onset (Matera 2004). NPARMS are generally small out-of-frame deletions or duplications and are typically associated with a more severe phenotype (Weese-Mayer et al. 2014). Notably, up to 10-25% of affected individuals have an asymptomatic parent who is mosaic for the familial mutation (Bachetti et al. 2011; Parodi et al. 2008).

The additional genes tested in this panel (RET, ASCL1/HASH1, EDN3, BDNF, PHOX2A, and BMP2) have also been associated with CCHS and HSCR, although their role is not totally clear. These genes are involved in early autonomic nervous system embryologic development and when mutated may have a role in the development of CCHS (Sasaki et al. 2003; Pontual L de. 2003; Bolk et al. 1996; Weese-Mayer et al. 2003).

Clinical Sensitivity - Sequencing with CNV PGxome

The clinical sensitivity for the PHOX2B gene in individuals with CCHS is >99% (Weese-Mayer et al. 2014). Low-level somatic mosaicism may be missed in regions analyzed only by Sanger sequencing. The clinical sensitivity of the other genes in this NGS panel is currently unknown for CCHS due to limited number of studies.

Large deletions in the PHOX2B gene account for < 1% of individuals affected with CCHS (Weese-Mayer et al. 2014). Clinical sensitivity for deletions of the RET gene is currently unknown due to the limited number of individuals studied with CCHS.

Testing Strategy

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

This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Sanger sequencing of the PHOX2B exon 3 is performed to detect the expansion of the polyalanine repeat region that are causative for CCHS.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

 

Indications for Test

Individuals who are clinically suspected or diagnosed with CCHS.

Genes

Official Gene Symbol OMIM ID
ASCL1 100790
BDNF 113505
BMP2 112261
EDN3 131242
PHOX2A 602753
PHOX2B 603851
RET 164761
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Bachetti T, Parodi S, Duca M, Santamaria G, Ravazzolo R, Ceccherini I. 2011. Low amounts of PHOX2B expanded alleles in asymptomatic parents suggest unsuspected recurrence risk in congenital central hypoventilation syndrome. Journal of Molecular Medicine 89: 505–513. PubMed ID: 21336852
  • Bolk et al. 1996.  Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome. Nat. Genet. 13: 395–396. PubMed ID: 8696331
  • Lai D., Schroer B. 2008. Journal of child neurology. 23: 341-3. PubMed ID: 18230845
  • Matera I. 2004. PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset Central Hypoventilation syndrome. Journal of Medical Genetics 41: 373–380. PubMed ID: 15121777
  • Parodi S, Bachetti T, Lantieri F, Duca MD, Santamaria G, Ottonello G, Matera I, Ravazzolo R, Ceccherini I. 2008. Parental origin and somatic mosaicism of PHOX2B mutations in Congenital Central Hypoventilation Syndrome. Human Mutation 29: 206–206. PubMed ID: 18157832
  • Pontual L de. 2003. Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse). Human Molecular Genetics 12: 3173–3180. PubMed ID: 14532329
  • Sasaki A, Kanai M, Kijima K, Akaba K, Hashimoto M, Hasegawa H, Otaki S, Koizumi T, Kusuda S, Ogawa Y, Tuchiya K, Yamamoto W, et al. 2003. Molecular analysis of congenital central hypoventilation syndrome. Human Genetics 114: 22–26. PubMed ID: 14566559
  • Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, Marazita ML. 2003. Idiopathic congenital central hypoventilation syndrome: Analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. American Journal of Medical Genetics 123A: 267–278. PubMed ID: 14608649
  • Weese-Mayer DE. et al. 2010. American journal of respiratory and critical care medicine. 181: 626-44. PubMed ID: 20208042
  • Weese-Mayer DE. et al. 2014. Congenital Central Hypoventilation Syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301600

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.

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

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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.

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