Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A Commentary on The importance of knowing from whence your PHOX2B mutation comes

Meguro et al.1 have more fully characterized the growing cohort of patients with Congenital Central Hypoventilation syndrome (CCHS) in Japan. Specifically, they have confirmed the autosomal dominant inheritance pattern2, 3 and described the incidence of somatic mosaicism or full mutation in parents of CCHS probands in the Japanese cohort (22%)—reflecting similar figures to the report (using the same methodology) as Bachetti et al.4

These results raise several important points in regard to genetic and physiologic testing procedures in CCHS families. First, the results emphasize the importance of genetic counseling for families in which a CCHS-causing PHOX2B mutation is identified. This report, and others, has identified families in which recurrence of these PHOX2B mutations and this disorder has occurred; typically an asymptomatic parent carried somatic mosaicism for a mutation, and without genetic counseling and proper genetic testing these families were without valuable information to advise family planning. Second, this report underscores the necessity of physicians to recommend and to complete thorough clinical and physiological evaluations to assure safety in these families. Here, Meguro et al. identified a family in which, after presentation of a single proband with a 25-alanine expansion mutation in PHOX2B, familial testing revealed the same mutation in two previous generations of the proband’s family. After this discovery, polysomnography revealed symptoms of late-onset CCHS in each of these mutation carriers, both previously considered asymptomatic. Third, these results reiterate the need to carefully consider the mechanism chosen for PHOX2B testing among probands and among parents of probands in order to optimize management, assure safety and physiologic stability, and to determine risk of recurrence in subsequent offspring. This report supports previous findings3, 4, 5 indicating inheritance of PHOX2B mutations from parental carriers with very low levels of somatic mosaicism (as low as 5% here). Although sequencing of the PHOX2B gene has become the most commonly available form of clinical testing in CCHS families, studies have shown it to be inadequate to identify low-level mosaicism.4, 5 Without proper testing procedures, no amount of clinical acumen or informed genetic counseling will be able to correctly inform families of recurrence risk. Figure 1 provides the algorithm to determine when and what type of PHOX2B genetic testing should be performed in parents of a CCHS proband. Though the American Thoracic Society (ATS) Statement on CCHS published in 20106 clearly recommended parental testing, it has become apparent that physicians are not consistently recommending parent testing for PHOX2B mutations, and they are not necessarily recommending the correct type of testing to identify mosaicism.

Figure 1

Algorithm to determine when and what type of PHOX2B genetic testing should be performed in parents of CCHS probands. PARM, polyalanine repeat expansion mutation; NPARM, non-polyalanine repeat expansion mutation. Reproduced with permission from Weese-Mayer et al.7 A full color version of this figure is available at the Journal of Human Genetics journal online.

Finally, identification of a cohort of this size in a Japanese population raises further questions about the actual incidence of CCHS worldwide. With the 2010 ATS Statement on CCHS, the international figure of 1000 cases was presented (though presumed to be an underestimate). Ethnic disparity among reported individuals with CCHS is apparent, with Caucasians more heavily represented than any other ethnicity.6 Additionally, the incomplete penetrance and variable phenotype identified here and elsewhere in individuals with the 20/25 genotype indicates there may be a growing number of individuals with unrecognized mild hypoventilation who will necessitate clinical acumen and intellectual curiosity to identify. As knowledge of this disease spreads and utilization of PHOX2B testing escalates, the perceived ‘rareness’ of CCHS may prove overstated.


  1. 1

    Meguro, T., Yoshida, Y., Hayashi, M., Toyota, K., Otagiri, T., Mochizuki, N. et al. Inheritance of polyalanine expansion mutation of PHOX2B in congenital central hypoventilation syndrome. J. Hum. Genet. 57, 335–337 (2012).

    CAS  Article  Google Scholar 

  2. 2

    Matera, I., Bachetti, T., Puppo, F., Di Duca, M., Morandi, F., Casiraghi, G. M. et al. PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset Central Hypoventilation syndrome. J. Med. Genet. 41, 373–380 (2004).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Weese-Mayer, D. E., Berry-Kravis, E. M., Zhou, L., Maher, B. S., Silvestri, J. M., Curran, M. E. et al. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2B. Am. J. Med. Genet. A. 123A, 267–278 (2003).

    Article  Google Scholar 

  4. 4

    Bachetti, T., Parodi, S., Di Duca, M., Santamaria, G., Ravazzolo, R. & Ceccherini, I. Low amounts of PHOX2B expanded alleles in asymptomatic parents suggest unsuspected recurrence risk in congenital central hypoventilation syndrome. J. Mol. Med. (Berl) 89, 505–513 (2011).

    Article  Google Scholar 

  5. 5

    Jennings, L. J., Yu, M., Zhou, L., Rand, C. M., Berry-Kravis, E. M. & Weese-Mayer, D. E. Comparison of PHOX2B testing methods in the diagnosis of congenital central hypoventilation syndrome and mosaic carriers. Diagn. Mol. Pathol. 19, 224–231 (2010).

    CAS  Article  Google Scholar 

  6. 6

    Weese-Mayer, D. E., Berry-Kravis, E. M., Ceccherini, I., Keens, T. G. & Trang, H. An official ATS clinical policy statement: congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am. J. Respir. Crit. Care. Med. 181, 626–644 (2010).

    CAS  Article  Google Scholar 

  7. 7

    Weese-Mayer, D. E., Patwari, P. P., Rand, C. M., Diedrich, A. M., Kuntz, N. L. & Berry-Kravis, E. M. Congenital central hypoventilation syndrome (CCHS) and PHOX2B mutations. in Primer on the Autonomic Nervous System, 3rd edn (eds Robertson D., Biaggioni I., Burnstock G., Low P.A., Paton J.F.R.) (San Diego, Academic Press, 2012).

    Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Casey M Rand.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rand, C., Weese-Mayer, D. A Commentary on The importance of knowing from whence your PHOX2B mutation comes. J Hum Genet 57, 345–346 (2012).

Download citation


Quick links