Congenital Central Hypoventilation Syndrome (CCHS) Panel

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 HSCR (Lai and Schroer 2008), but neither term is 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 mainly caused by PHOX2B mutations. PHOX2B encodes a transcription factor that is involved in the normal sympathetic neuronal development and catecholamine synthesis. Two major types of mutations occur in PHOX2B. These are heterozygous polyalanine repeat expansion mutations (PARMs) and non-polyalanine repeat expansion mutations (NPARMs). An unaffected individual generally is homozygous for 20 alanine repeats. Less than 20 repeats have also been reported and are generally considered benign, although the repeat numbers have not been extensively studied with respect to breathing deficit or autonomic dysregulation (Weese-Mayer et al. 2014). Individuals who are heterozygous for reported 24-33 alanine repeats are affected with CCHS, with increasing allele size correlating with increasing disease severity and earlier age of onset (Matera 2004). NPARMS are generally small out-of-frame deletions or duplications and are typically associated with a more severe phenotype (Weese-Mayer et al. 2014). Notably, up to 10-25% of affected individuals have an asymptomatic parent who is mosaic for the familial mutation (Bachetti et al. 2011; Parodi et al. 2008).

The additional genes tested in this panel (RET, ASCL1/HASH1, EDN3, BDNF, PHOX2A, and BMP2) have also been associated with CCHS and HSCR, although their role is not totally clear. These genes are involved in early autonomic nervous system embryologic development and when mutated may have a role in the development of CCHS (Sasaki et al. 2003; Pontual L de. 2003; Bolk et al. 1996; Weese-Mayer et al. 2003).

The clinical sensitivity for the PHOX2B gene in individuals with CCHS is >99% (Weese-Mayer et al. 2014). Low-level somatic mosaicism may be missed in regions analyzed only by Sanger sequencing. The clinical sensitivity of the other genes in this NGS panel is currently unknown for CCHS due to limited number of studies.

Large deletions in the PHOX2B gene account for < 1% of individuals affected with CCHS (Weese-Mayer et al. 2014). Clinical sensitivity for deletions of the RET gene is currently unknown due to the limited number of individuals studied with CCHS.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).

Sanger sequencing of PHOX2B exon 3 is performed to detect expansions of the polyalanine repeat region that are causative for CCHS. However, lack of amplification of expanded alleles has been reported in the literature due to the genomic context of this region (Matera et al. 2004. PubMed ID: 15121777). Therefore, we cannot rule out the possibility of allele dropout within this region. This test is also unable to determine degrees of mosaicism for the polyalanine repeat region.

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).