Congenital Central Hypoventilation Syndrome (CCHS) via the PHOX2A Gene

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 these 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).

Congenital Central Hypoventilation Syndrome is inherited in an autosomal dominant manner and is usually caused by PHOX2B mutations. PHOX2A has also been associated with CCHS and HSCR, although its role is not totally clear. This gene is involved in early autonomic nervous system embryologic development and when mutated has been associated with the development of CCHS (Sasaki et al. 2003; Weese-Mayer et al. 2014). The PHOX2A protein product is involved in the development of the autonomic nervous system. It does so by regulating the expression of tyrosine hydroxylase and dopamine beta-hydroxylase, and it has also been suggested that it is involved in the expression of RET (de Pontual 2003). In addition to CCHS, pathogenic variants in PHOX2A have also been associated with autosomal recessive congenital fibrosis of the extraocular muscles (Andrews et al. 2011).

Clinical sensitivity of mutations in this gene in CCHS is currently unknown due to the rarity of this disease.

This test provides full coverage of all coding exons of the PHOX2A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).