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.


Testing Benefits and Implications

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


California


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

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


Georgia


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



Illinois


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




Massachusetts


BOSTON
Parabase Genomics
27 Drydock Avenue, 2nd Floor
Boston, MA 02210
Phone: 857-288-0838
Fax: 866-604-9369

CAMBRIDGE
Laboratory for Molecular Medicine,
Partners HealthCare Personalized Medicine

65 Landsdowne St.
Cambridge, MA 02139
Phone: 617-768-8500
Fax: 617-768-8513



Ohio


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




Pennsylvania


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




Utah


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




Wisconsin


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



International Testing Centers


Canada


ALBERTA
CEN4GEN Institute for Genomics and Molecular Diagnostics
6756 75 Street NW
Edmonton, AB T6E 6T9
Canada
Phone: 1-844-236-4436
Fax: 1-587-329-9566




Finland


HELSINKI
Blueprint Genetics
Tukholmankatu 8, Biomedicum 2U
Helsinki 00290
Finland
Phone: US +1-650-452-9340
Fax: US +1-650-636-9779




France


PARIS
Medical Genetics
Prof. Dr. Arnold Munnich
Hôpital Necker – Enfants Malades
149 Rue de Sèvres
75015 Paris, France
Phone: 01-44-49-40-00




Germany


BERLIN
Max Planck Institute for Molecular Genetics
Unversitatsklinikum Charite
Ihnestraße 63-73
14195 Berlin, Germany
Phone: +49-30-8413-1449
Fax: +49-30-8413-1207




Italy


GENOA
Laboratory of Molecular Genetics, IRCCS
Prof. Dr. Isabella Ceccherini; Prof. Dr. Tiziana Bachetti
Giannina Gaslini Institute
Via Gerolamo Gaslini, 5
16148 Genoa, Italy
Phone: +39-010-56361




Japan


YAMAGATA
Yamagata University School of Medicine
Kiyoshi Hayasaka, MD, PhD; Ayako Sasaki, MD, PhD
Department of Pediatrics
2-2-2 Iida-nishi
Yamagata 990-9585, Japan
Phone: +81-23-633-1122




Portugal


PORTO
CGC Genetics
Rua Sá da Bandeira, 706
Porto 4000-432
Porto, Portugal
Phone: +351223389900
Fax: +351222088710




Spain


BARCELONA
Reference Laboratory Genetics
Pablo Iglesias, 57-59
L´Hospitalet de Llobregat
Barcelona
08740 Barcelona, Spain
Phone: +34-932593700
E-mail: genetics@referencelaboratory.es




Sweden


STOCKHOLM
Research Group for Malformation Genetics,
Department of Molecular Medicine and Surgery

Karolinska University Hospital, Solna,
SE-171 76 Stockholm, Sweden
Phone: +46-8-517-777-05
E-mail: agneta.nordenskjold@karolinska.se