Department of Prenatal Diagnosis Center, Maternity and Child Health Care Affiliated Hospital, Jiaxing University, Jiaxing 314000, China.
Department of Prenatal Diagnosis Center, Maternity and Child Health Care Affiliated Hospital, Jiaxing University, Jiaxing 314000, China.
Gene. 2024 Jun 15;911:148358. doi: 10.1016/j.gene.2024.148358. Epub 2024 Mar 11.
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.
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.
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.
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.
配对同源盒 2B（PHOX2B）被认为是先天性中枢性低通气综合征（CCHS）的致病基因，CCHS 是一种显性遗传疾病，其特征是中枢性呼吸控制受损，随后在睡眠中出现低通气。
本文报道了一个有复发性严重 CCHS 的家系。通过全外显子组测序（WES）、Sanger 测序和数字液滴 PCR（ddPCR）确认了潜在的致病基因突变。此外，应先证者母亲的要求，在她第四次妊娠 20 周时对其进行了产前诊断。
先证者及其哥哥均为 PHOX2B 多聚丙氨酸扩展变异的携带者：c.744_758dupCGCGGCAGCGGCGGCGGCGGC。Sanger 测序显示，先证者的父亲在基因位置存在小变异峰，提示可能存在体细胞嵌合现象。此外，ddPCR 结果显示先证者的父亲存在生殖系嵌合，嵌合比例为 14.3%。值得注意的是，胎儿中未检测到 p.(Ala241[26])变异。
这些发现对改善 CCHS 家系的遗传咨询具有重要意义，因为它们表明即使没有 CCHS 症状的父母也可能存在体细胞嵌合，需要进行仔细的遗传咨询，并考虑对后续妊娠进行产前检测。
