Central Hypoventilation Syndrome: PHOX2B Polyalanine Repeat

Clinical Information

Central hypoventilation syndrome is an autosomal dominant disorder that is characterized by shallow breathing with occasional apnea. Age of onset is typically in the newborn period, and the features are due to autonomic dysregulation. Other symptoms may include cardiac arrhythmias, temperature instability, profuse sweating, and diminished reactivity of the pupils. Hirschsprung disease occurs in up to 20% of affected individuals with severe constipation in a significant number of additional patients. An increased risk for neural crest tumors such as neuroblastoma, ganglioneuroma, and ganglioneuroblastoma is present with a higher risk among individuals with non-polyalanine expansions in PHOX2B. Ventilatory support is required throughout life although some individuals will only require support during sleep.

Technical Information

Genomic DNA is used to amplify the region of interest of the PHOX2B gene by PCR; fragments are analyzed by capillary gel electrophoresis and compared with appropriate controls to identify expansion in the polyalanine tract. An abnormal result from fragment analysis is confirmed by Sanger sequencing.

Specimen Requirements

• The preferred sample type is 3-4 ml of peripheral blood collected in an EDTA (purple top) tube. Dried blood spots, extracted DNA, and saliva are also accepted for this test. Blood and saliva kits are available by request.
• Approximately 75 µL of blood should be applied to each of the five circles on a filter paper dried blood spot card. Allow blood to dry for at least 4 hours before shipping.
• Send approximately 5 µg of extracted DNA at a requested concentration of 90-130 ng/µl.
• Saliva samples must be submitted in an approved saliva kit.

Transport Instructions

• The blood specimen should be kept at room temperature and delivered via overnight shipping. If shipment is delayed by one or two days, the specimen should be refrigerated and shipped at room temperature. Do not freeze the specimen. Samples collected on Friday can be safely designated for Monday delivery.
• DBS cards should be shipped at room temperature.
• Extracted DNA should be sent at room temperature via overnight delivery.
• Saliva is stable at room temperature and can be delivered via overnight or ground shipping.