Conflicts of interest: None.
Article first published online: 20 JUL 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 158A, Issue 9, pages 2297–2301, September 2012
How to Cite
Rand, C. M., Yu, M., Jennings, L. J., Panesar, K., Berry-Kravis, E. M., Zhou, L. and Weese-Mayer, D. E. (2012), Germline mosaicism of PHOX2B mutation accounts for familial recurrence of congenital central hypoventilation syndrome (CCHS). Am. J. Med. Genet., 158A: 2297–2301. doi: 10.1002/ajmg.a.35499
How to Cite this Article: Rand CM, Yu M, Jennings LJ, Panesar K, Berry-Kravis EM, Zhou L, Weese-Mayer DE. 2012. Germline mosaicism of PHOX2B mutation accounts for familial recurrence of congenital central hypoventilation syndrome (CCHS). Am J Med Genet Part A. 158A:2297–2301.
- Issue published online: 24 AUG 2012
- Article first published online: 20 JUL 2012
- Manuscript Accepted: 6 MAY 2012
- Manuscript Received: 14 FEB 2012
- Chicago Community Foundation PHOX2B Patent Fund
- congenital central hypoventilation syndrome;
- Ondine's Curse;
- germline mosaicism
Congenital central hypoventilation syndrome (CCHS), a rare disorder characterized by alveolar hypoventilation and autonomic dysregulation, is caused by mutations in the PHOX2B gene. Most mutations occur de novo, but recent evidence suggests that up to 25% are inherited from asymptomatic parents with somatic mosaicism for these mutations. However, to date, germline mosaicism has not been reported. This report describes a family with recurrence of PHOX2B mutation-confirmed CCHS due to germline mosaicism. The first occurrence was a baby girl, noted on day 2 of life to have multiple episodes of apnea, bradycardia, and cyanosis while breathing room air. PHOX2B gene testing confirmed the diagnosis of CCHS with a heterozygous polyalanine repeat expansion mutation (PARM); genotype 20/27 (normal 20/20). Both parents tested negative for this mutation using fragment analysis (limit of detection <1%). Upon subsequent pregnancy [paternity confirmed using short tandem repeat (STR) analysis], amniocentesis testing identified the PHOX2B 20/27 genotype, confirmed with repeat testing. Elective abortion was performed at 21.5 weeks gestation. Testing of abortus tissue confirmed amniocentesis testing. The PHOX2B 20/27 expansion was not observed in a paternal sperm sample. This case represents the first reported family with recurrence of PHOX2B mutation-confirmed CCHS without detection of a parental carrier state or mosaicism, confirming the previously hypothesized possibility of germline mosaicism for PHOX2B mutations. This is an important finding for genetic counseling of CCHS families, suggesting that even if somatic mosaicism is not detected in parental samples, there is still reason for careful genetic counseling and consideration of prenatal testing during subsequent pregnancies. © 2012 Wiley Periodicals, Inc.