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Congenital Central Hypoventilation Syndrome (CCHS) via the PHOX2B Gene

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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
PHOX2B 81404 81404,81403 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8967PHOX2B81404 81404,81403 $990 Order Options and Pricing

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Greg Fischer, PhD

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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Greg Fischer, PhD

Clinical Features and Genetics

Indications for Test

Individuals who are clinically suspected or diagnosed with CCHS.

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 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 Hirschsprung disease (Lai and Schroer 2008), but both terms are not 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 is 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 include 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 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).

Clinical Sensitivity - Sequencing with CNV PG-Select

Clinical sensitivity is near 99% for detecting NPARMS in affected individuals, with ~92% of mutations related to PPARMS and ~8% to NPARMS (Weese-Mayer et al. 2014). Individuals who have low-level somatic mosaicism may be missed via sequencing.

Clinical sensitivity for deletions of the PHOX2B gene is < 1% of individuals affected with CCHS (Weese-Mayer et al. 2014).

Testing Strategy

Sanger sequencing of PHOX2B exon 3 is performed to detect expansions of the polyalanine repeat region that are causative for CCHS. However, lack of amplification of expanded alleles has been reported in the literature due to the genomic context of this region (Matera et al. 2004. PubMed ID: 15121777).  Therefore, we cannot rule out the possibility of allele dropout within this region. This test is also unable to determine degrees of mosaicism for the polyalanine repeat region.

This test provides full coverage of all coding exons of the PHOX2B gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Individuals who are clinically suspected or diagnosed with CCHS.

Gene

Official Gene Symbol OMIM ID
PHOX2B 603851
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Congenital Central Hypoventilation syndrome AD 209880

Related Tests

Name
Congenital Central Hypoventilation Syndrome (CCHS) via the ASCL1 Gene
Congenital Central Hypoventilation Syndrome (CCHS) via the BMP2 Gene
Congenital Central Hypoventilation Syndrome (CCHS) via the PHOX2A Gene
Hereditary Neuroblastoma via the PHOX2B Gene

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
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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

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