Abstract
Congenital central hypoventilation syndrome (CCHS; MIM 209880) is caused mostly by dominant alanine expansion (most prevalent is 7-alanine expansion) mutations in PHOX2B. More than 90% of the alanine expansion mutations had been considered to be de novo due to unequal crossover during gametogenesis. However, a recent report stated that 25% of patients inherited the alanine-expanded allele from their parents with somatic mosaicism or constitutive mutation. We studied inheritance in 45 unrelated families, and found that one patient (2%) inherited 5-alanine expansion mutation from a parent with late-onset central hypoventilation syndrome and nine patients (20%) inherited 5- to 7-alanine expansion mutation from apparently asymptomatic parents with somatic mosaicism. Analysis using a sensitive method would be recommended to all parents of CCHS proband due to high incidence of somatic mosaicism. The absence of an alanine-contracted allele (expected counterpart allele in unequal crossover) and the highest prevalence of 6-alanine expansion mutation in somatic mosaicism suggest that the somatic mosaicism is likely caused by a mechanism other than an unequal crossover, such as a replication mechanism.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B . et al Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat. Genet. 33, 459–461 2003.
Sasaki, A., Kanai, M., Kijima, K., Akaba, K., Hashimoto, M., Hasegawa, H. et al Molecular analysis of congenital central hypoventilation syndrome. Hum. Genet. 114, 22–26 2003.
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.
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 genespertinent to early autonomic nervous system embryologic development and identificationof mutations in PHOX2b. Am. J. Med. Genet. A 123A, 267–278 2003.
Trochet, D., O’Brien, L. M., Gozal, D., Trang, H., Nordenskjold, A., Laudier, B. et al PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. Am. J. Hum. Genet. 76, 421–426 2005.
Berry-Kravis, E. M., Zhou, L., Rand, C. M., Weese-Mayer, D. E. Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am. J. Respir. Crit. CareMed. 174, 1139–1144 2006.
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.
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.
Trochet, D., Hong, S. J., Lim, J. K., Brunet, J. F., Munnich, A., Kim, K. S. et al Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Hum. Mol. Genet. 14, 3697–3708 2005.
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.
Weese-Mayer, D. E., Berry-Kravis, E. M., Ceccherini, I., Keens, T. G., Dariu, A., Loghmanee, D. A. et al An oficial ATS clinical policy statement: Congenital central hypoventilation syndrome. Genetic basis, diagnosis, and management. Am. J. Respir. Crit. Care Med. 181, 626–644 2010.
Trochet, D., de Pontual, L., Straus, C., Gozal, D., Trang, H., Landrieu, P. et al PHOX2B germline and somatic mutations in late-onset central hypoventilation syndrome. Am. J. Respir. Crit. Care Med. 177, 906–911 2008.
Warren, S. T. Polyalanine expansion in synpolydactyly might result from unequal crossing-over of HOXD13. Science 275, 408–409 1997.
Arai, H., Otagiri, T., Sasaki, A., Hashimoto, T., Umetsu, K., Tokunaga, K. et al De novo polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: unequal sister chromatid exchange during paternal gametogenesis. J. Hum. Genet 52, 921–925 2007.
Arai, H., Otagiri, T., Sasaki, A., Umetsu, K., Hayasaka, K. Polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: rs17884724:A>C is associated with 7-alanine expansion. J. Hum. Genet 55, 4–7 2009.
Horiuchi, H., Sasaki, A., Osawa, M., Kijima., K., Ino, Y., Matoba, R. et al Sensitive detection of polyalanine expansions in PHOX2B by polymerase chain reaction using bisulfite-converted DNA. J. Mol. Diagn. 7, 638–640 2005.
Mirkin, S. M. Expandable DNA repeats and human disease. Nature 447, 932–940 2007.
Acknowledgements
We thank the patients and their families for their cooperation. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Culture and Sports of Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Meguro, T., Yoshida, Y., Hayashi, M. et al. Inheritance of polyalanine expansion mutation of PHOX2B in congenital central hypoventilation syndrome. J Hum Genet 57, 335–337 (2012). https://doi.org/10.1038/jhg.2012.27
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2012.27
Keywords
This article is cited by
-
Transitional care and clinical management of adolescents, young adults, and suspected new adult patients with congenital central hypoventilation syndrome
Clinical Autonomic Research (2023)
-
Adult-onset congenital central hypoventilation syndrome due to PHOX2B mutation
Acta Neurologica Belgica (2021)
-
Congenital central hypoventilation syndrome: a bedside-to-bench success story for advancing early diagnosis and treatment and improved survival and quality of life
Pediatric Research (2017)
-
Genotype–phenotype relationship in Japanese patients with congenital central hypoventilation syndrome
Journal of Human Genetics (2015)
-
A Commentary on The importance of knowing from whence your PHOX2B mutation comes
Journal of Human Genetics (2012)
