背景:配对型同源异型盒2B(PHOX2B)被认为是先天性中枢通气不足综合征(CCHS)的致病基因,以中枢呼吸控制受损和随后睡眠期间通气不足为特征的显性遗传性疾病。
方法:这里,我们介绍了一个患有复发性严重CCHS的家庭。通过全外显子组测序(WES)证实了潜在的致病遗传变异,桑格测序,和液滴数字PCR(ddPCR)。此外,应要求,先证者的母亲在第四次怀孕20周时进行了产前诊断。
结果:先证者和她的兄弟都是PHOX2B聚丙氨酸扩展变体的携带者:c.744_758dupCGGGCAGCGGGCGGCGGC。Sanger测序显示先证者的父亲在基因位置有一个小的变异峰,暗示潜在的躯体镶嵌。此外,ddPCR结果显示先证者的父亲有种系镶嵌,镶嵌比例为14.3%。值得注意的是,在胎儿中未检测到p.(Ala241[26])变异。
结论:这些发现对改善CCHS家族的遗传咨询具有重要意义,因为它们表明即使没有CCHS症状的父母也可能具有体细胞嵌合体,需要仔细的遗传咨询和考虑随后怀孕的产前检查。
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.