Congenital Central Hypoventilation Syndrome (CCHS) via the ASCL1 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 (HSCR) 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 pathogenic variants. ASCL1 has also been associated with CCHS and HSCR, although its role is not totally clear. This gene is a transcription factor that co-regulates differentiation of the autonomic nervous system with PHOX2B (Ide et al. 2005). Using an in vitro model, one study demonstrated that three ASCL1 variants (one missense and two small deletions) from individuals with CCHS were found to induce the impairment of noradrenergic neuronal development (de Pontual 2003). Thus far in ASCL1, only these three variants have been associated with CCHS.

The clinical sensitivity for ASCL1 in CCHS is currently unknown due to the limited number of studies. Analytical sensitivity should be high because all pathogenic variants reported are detectable by sequencing.

This test provides full coverage of all coding exons of the ASCL1 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).