Recurrence of CCHS-associated PHOX2B Poly-Alanine expansion variant due to paternal mosaicism

Gene. 2024 Jun 15:911:148358. doi: 10.1016/j.gene.2024.148358. Epub 2024 Mar 11.


Background: Paired-like Homeobox 2B (PHOX2B) is considered the causative gene of Congenital Central Hypoventilation Syndrome (CCHS), a dominant genetic disorder characterized by impaired central respiratory control and subsequent hypoventilation during sleep.

Methods: Herein, we present a family with recurrent severe CCHS. The potential causative genetic variant was confirmed through Whole-Exome Sequencing (WES), Sanger sequencing, and droplet digital PCR (ddPCR). Furthermore, prenatal diagnosis was performed on the proband's mother at 20 weeks of her fourth pregnancy upon request.

Results: The proband and her brother were both carriers of the PHOX2B polyalanine expansion variant: c.744_758dupCGCGGCAGCGGCGGCGGCGGC. Sanger sequencing revealed that the proband's father had a small variant peak in the gene position, implying potential somatic mosaicism. In addition, ddPCR results showed that the proband's father had germline mosaicism, with a mosaicism proportion of 14.3%. Notably, the detect p.(Ala241[26]) variant was not detected in the fetus.

Conclusions: These findings have important implications for improving genetic counseling of CCHS families as they suggest that even parents without CCHS symptoms may have somatic chimerism, necessitating careful genetic counseling and consideration of prenatal testing for subsequent pregnancies.

Keywords: Congenital Central Hypoventilation Syndrome (CCHS); Disease Recurrence; Genetic Counseling; PHOX2B Polyalanine Expansion; Somatic Mosaicism.

MeSH terms

  • Alanine
  • Fathers
  • Female
  • Homeodomain Proteins* / genetics
  • Humans
  • Hypoventilation* / congenital*
  • Hypoventilation* / genetics
  • Male
  • Mosaicism
  • Mutation
  • Pregnancy
  • Sleep Apnea, Central*
  • Transcription Factors / genetics


  • Homeodomain Proteins
  • Alanine
  • Transcription Factors

Supplementary concepts

  • Congenital central hypoventilation syndrome