Confirming the Diagnosis: Blood Testing

by Melinda Riccitelli, CCHS mom and professor of Biology at Mira Costa College, CA

CCHS is inherited in an autosomal dominant pattern. However, the majority of cases are caused by de novo mutations, meaning they occur for the first time in the affected individual in that family. Approximately 92% of people with CCHS have a type of mutation called a polyalanine repeat expansion mutation (PARM). Within coding exon 3 of the PHOX2B gene, there is a repeating region that results in a string of an amino acid called alanine. Normally, there are 20 alanine repeats or less in this exon of PHOX2B. In people with CCHS, there can be 25-33 repeats. The remaining ~8% of patients have non-polyalanine repeat expansion mutations (NPARMs), including DNA sequence alterations or frameshift mutations.

Genetic testing can be very useful due to the strong genotype-phenotype correlations in CCHS. Mutation type and repeat length generally correlate with disease severity. NPARMs can cause more severe symptoms and are associated with increased frequencies of Hirschsprung disease, neural crest tumors, and continuous ventilator dependence. Similarly, large repeat expansions correlate with more severe respiratory concerns and a higher risk of Hirschsprung disease and tumors, when compared to shorter repeat expansions. Other genotype-phenotype associations exist as well, and can involve other organ systems.

The American Thoracic Society has published a clinical policy statement regarding PHOX2B genetic testing in those suspected to have CCHS, as well as in their at-risk relatives.

Benefits of Genetic Testing Include:

• Direct impact on prognosis/medical care/treatment/surveillance due to knowledge of the specific PHOX2B mutation a person has (because of the genotype-phenotype correlation in CCHS)
• Diagnostic confirmation in patients suspected to have congenital or late-onset CCHS
• Parental testing to rule out risk for late-onset symptoms
• Screening to adjust medical management in at-risk relatives

There are several labs in the US that can test for the PHOX2B gene mutation. Below is partial list of testing centers in the US, Canada, Europe and Japan.

U.S. Testing Centers

ALISA VIEJO
Ambry Genetics^®
15 Argonaut
Aliso Viejo, CA 92656
Phone: 949-900-5500
Fax: 949-900-5501

ORANGE
Genetics Center
211 S. Main Street
Orange, CA 92868
Phone: 714-288-3500
Fax: 714-288-8525

San Francisco
Blueprint Genetics
1268 Missouri Street
San Francisco, CA 94107
Phone: 650-452-9340 Ext. 0
Fax: 650-446-7790

TEMPLE CITY
Fulgent Diagnostics
4978 Santa Anita Ave, Suite 205
Temple City, CA 91780
Phone: 626-350-0537
Fax: 626-454-1667

ATLANTA
Emory University School of Medicine,
Emory Molecular Genetics Laboratory
12165 N Decatur Rd
Atlanta, GA 30033
Phone: 404-778-8499
Fax: 404-778-8559

ATLANTA
MNG Laboratories/Medical Neurogenetics
5424 Glenridge Dr. NE
Atlanta, GA 30342
Phone: 678-225-0222
Fax: 678-225-0212

CHICAGO
Lurie’s Children’s Hospital
(formerly Children’s Memorial Hospital)
HLA and Molecular Diagnostic Laboratories
2515 N. Clark Street
Deming Building, Room 5027
Chicago, IL 60614
Phone: 312-227-6130
Fax: 312-227-9456

CAMBRIDGE
Laboratory for Molecular Medicine,
Partners HealthCare Personalized Medicine
65 Landsdowne St.
Cambridge, MA 02139
Phone: 617-768-8500
Fax: 617-768-8513

MIDDLEFIELD
DDC Clinic Molecular Diagnostics Laboratory
14567 Madison Road
Middlefield, OH 44062
Phone: 440-632-5532
Fax: 440-632-1697

PHILADELPHIA
Children’s Hospital of Philadelphia (CHOP)
3615 Civic Center Blvd
Philadelphia, PA 19104
Phone: 267-426-1447
Fax: 215-590-2156

SALT LAKE CITY
ARUP Laboratories, Molecular Genetics Laboratory
500 Chipeta Way
Salt Lake City, UT 84108
Phone: 800-242-2787 x2141
Fax: 801-584-5052

MARSHFIELD
Prevention Genetics, Clinical DNA Testing and DNA Banking
3800 S. Business Park Ave.
Marshfield, WI 54449
Phone: 715-387-0484
Fax: 715-384-3661