Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA is also acceptable.
Unacceptable Conditions
Heparinized specimens, severely hemolyzed specimens, frozen, clotted or possibly commingled specimens, blood in non-sterile or leaky containers, mislabeled or inappropriately labeled specimens.
Storage/Transport Temperature
For CHOP Phlebotomy: Samples can be collected throughout the week. Samples collected on weekends or holidays are held in Central Labs and sent to the Genomic Diagnostic Lab the following business day.
For External Clients: Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday, optimally within 24 hours of collection.
Please contact the lab (267-426-1447) with questions regarding non-blood specimens.
Volume Required
5 ml whole blood or 1 ug DNA
Minimum Required
3 ml whole blood
Phlebotomy Draw
Yes
Clinical Features
Classic congenital central hypoventilation syndrome (CCHS) is characterized by adequate ventilation while the affected individual is awake and by hypoventilation with normal respiratory rates and shallow breathing during sleep; more severely affected individuals hypoventilate when both awake and asleep. Both phenotypes present in the newborn period. Children with CCHS often have physiologic and anatomic manifestations of a generalized autonomic nervous system dysfunction/dysregulation (ANSD); a subset (16-20%) have altered development of neural crest-derived structures (i.e., Hirschsprung disease).
Tumors of neural crest origin including neuroblastoma, ganglioneuroma, and ganglioneuroblastoma, are observed overall in 5%-6% of children with CCHS [Trochet et al 2005b, Berry-Kravis et al 2006]. The risk of a neural crest tumor is highest in children with Non-polyalanine repeat expansion mutations (~50% will develop a neuroblastoma), and rare among children with polyalanine repeat expansion mutations (low but apparent risk is in those with 20/29-20/33 genotypes). The tumors can present at variable ages: neuroblastoma typically before age two years; ganglioneuromas later as incidental findings. Tumor-related deaths are uncommon.
Performing Lab
Division of Genomic Diagnostics
Performed
Mon - Fri 9:00am to 4:00pm
Reported
28 days
Detection Rate
Mutations in the PHOX2B gene have been identified in >92% of patients with a clinical diagnosis of CCHS.
Utility
The clinical utility of the assay is in confirming the clinical diagnosis, assessing the risk to other first degree relatives, genotyping at risk family members (such as parents) for already identified mutations and confirming their risk for late onset CCHS. It is also useful in establishing the need for continued clinical surveillance of the patient for the purpose of early detection of tumors.
We offer DNA sequence analysis of the entire coding region of the PHOX2B gene and fragment analysis of exon 3 to assess for polyalanine repeat length. PCR amplification and sequencing is performed on all coding exons including splice junctions. The patient's gene sequence is then compared to a reference sequence. Sequence variants are classified as mutations, variants of unknown significance or benign variants unrelated to disease. Variants of unknown significance may warrant further studies in the patient and other family members. Large deletions, mutations in promoters, deep intronic regions and other regulatory regions will not be identified with this assay.
Molecular Testing Notes
CCHS is inherited in an autosomal dominant manner. PHOX2B maps to chromosome 4p12 and encodes a highly conserved homeobox domain transcription factor. Most individuals with CCHS are heterozygous for de novo repeat expansions in PHOX2B (Paired mesoderm homeobox protein 2B). Approximately 5% of individuals with CCHS have an asymptomatic parent who has somatic mosaicism for a PHOX2B mutation.
CPT Codes
81404x2
Billing (EAP) Codes
806932
PHOX2B Seq Analysis
807123
PHOX2B Fragment Analysis
Collection
Collect
Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA is also acceptable.
Unacceptable Conditions
Heparinized specimens, severely hemolyzed specimens, frozen, clotted or possibly commingled specimens, blood in non-sterile or leaky containers, mislabeled or inappropriately labeled specimens.
Storage/Transport Temperature
For CHOP Phlebotomy: Samples can be collected throughout the week. Samples collected on weekends or holidays are held in Central Labs and sent to the Genomic Diagnostic Lab the following business day.
For External Clients: Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday, optimally within 24 hours of collection.
Please contact the lab (267-426-1447) with questions regarding non-blood specimens.
Volume Required
5 ml whole blood or 1 ug DNA
Minimum Required
3 ml whole blood
Phlebotomy Draw
Yes
Ordering
Clinical Features
Classic congenital central hypoventilation syndrome (CCHS) is characterized by adequate ventilation while the affected individual is awake and by hypoventilation with normal respiratory rates and shallow breathing during sleep; more severely affected individuals hypoventilate when both awake and asleep. Both phenotypes present in the newborn period. Children with CCHS often have physiologic and anatomic manifestations of a generalized autonomic nervous system dysfunction/dysregulation (ANSD); a subset (16-20%) have altered development of neural crest-derived structures (i.e., Hirschsprung disease).
Tumors of neural crest origin including neuroblastoma, ganglioneuroma, and ganglioneuroblastoma, are observed overall in 5%-6% of children with CCHS [Trochet et al 2005b, Berry-Kravis et al 2006]. The risk of a neural crest tumor is highest in children with Non-polyalanine repeat expansion mutations (~50% will develop a neuroblastoma), and rare among children with polyalanine repeat expansion mutations (low but apparent risk is in those with 20/29-20/33 genotypes). The tumors can present at variable ages: neuroblastoma typically before age two years; ganglioneuromas later as incidental findings. Tumor-related deaths are uncommon.
Performing Lab
Division of Genomic Diagnostics
Performed
Mon - Fri 9:00am to 4:00pm
Reported
28 days
Detection Rate
Mutations in the PHOX2B gene have been identified in >92% of patients with a clinical diagnosis of CCHS.
Utility
The clinical utility of the assay is in confirming the clinical diagnosis, assessing the risk to other first degree relatives, genotyping at risk family members (such as parents) for already identified mutations and confirming their risk for late onset CCHS. It is also useful in establishing the need for continued clinical surveillance of the patient for the purpose of early detection of tumors.
We offer DNA sequence analysis of the entire coding region of the PHOX2B gene and fragment analysis of exon 3 to assess for polyalanine repeat length. PCR amplification and sequencing is performed on all coding exons including splice junctions. The patient's gene sequence is then compared to a reference sequence. Sequence variants are classified as mutations, variants of unknown significance or benign variants unrelated to disease. Variants of unknown significance may warrant further studies in the patient and other family members. Large deletions, mutations in promoters, deep intronic regions and other regulatory regions will not be identified with this assay.
Molecular Testing Notes
CCHS is inherited in an autosomal dominant manner. PHOX2B maps to chromosome 4p12 and encodes a highly conserved homeobox domain transcription factor. Most individuals with CCHS are heterozygous for de novo repeat expansions in PHOX2B (Paired mesoderm homeobox protein 2B). Approximately 5% of individuals with CCHS have an asymptomatic parent who has somatic mosaicism for a PHOX2B mutation.
