Serra Alexandre, Görgens Heike, Alhadad Karin, Fitze Guido, Schackert Hans K
Department of Surgery (Section Pediatric Surgery), University of Ulm, Ulm, Germany.
Ann Hum Genet. 2010 Jul;74(4):369-74. doi: 10.1111/j.1469-1809.2010.00577.x. Epub 2010 Apr 25.
Central congenital hypoventilation syndrome (CCHS) is an autonomous control disease producing hypoventilation, high PaCO(2), and low PaO(2) during quiet sleep. The main gene variants detected in CCHS are mutations in the PHOX2b gene in up to 97% of isolated cases. However, CCHS is sometimes associated with autonomic diseases such as Hirschsprung disease (HSCR). Since genomic rearrangements in particularly sensitive areas of the RET protooncogene and/or associated genes may account for the CCHS/HSCR phenotype in patients without other detectable RET variants, the aim of the present study was to identify rearrangements in the coding sequence of RET as well as in three HSCR-associated genes (ZEB2, EDN3 and GDNF) in CCHS/HSCR patients by using Multiplex Ligation-dependent Probe Amplification (MLPA). We have screened 27 CCHS and 11 CCHS/HSCR patients for genomic rearrangements in RET, ZEB2, EDN3 and GDNF and did not identify any deletion or amplification in these four genes in all patients. We conclude that genomic rearrangements in RET are rare and were not responsible for the CCHS/HSCR phenotype in individuals without identifiable germline RET variants in our group of patients, yet this possibility cannot be excluded altogether given the size of the cohort.
中枢性先天性低通气综合征（CCHS）是一种自主控制疾病，在安静睡眠期间会导致通气不足、高碳酸血症（高PaCO₂）和低氧血症（低PaO₂）。在CCHS中检测到的主要基因变异是PHOX2b基因突变，在高达97%的散发病例中存在该突变。然而，CCHS有时与诸如先天性巨结肠病（HSCR）等自主神经疾病相关。由于RET原癌基因和/或相关基因的特定敏感区域的基因组重排可能导致无其他可检测到的RET变异的患者出现CCHS/HSCR表型，本研究的目的是通过多重连接依赖探针扩增技术（MLPA）鉴定CCHS/HSCR患者RET编码序列以及三个与HSCR相关基因（ZEB2、EDN3和GDNF）中的重排情况。我们对27例CCHS患者和11例CCHS/HSCR患者进行了RET、ZEB2、EDN3和GDNF基因组重排的筛查，在所有患者中均未发现这四个基因有任何缺失或扩增。我们得出结论，在我们的患者群体中，RET基因的基因组重排在无可识别的种系RET变异的个体中很少见，且并非CCHS/HSCR表型的原因，但鉴于队列规模，这种可能性不能完全排除。
