Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Hospital Universitario Virgen del Rocío, (Manuel Siurot s/n), Seville, (41013), Spain.
BMC Med Genet. 2009 Nov 19;10:119. doi: 10.1186/1471-2350-10-119.
Hirschsprung disease (HSCR) is a congenital malformation of the hindgut produced by a disruption in neural crest cell migration during embryonic development. HSCR has a complex genetic etiology and mutations in several genes, mainly the RET proto-oncogene, have been related to the disease. There is a clear predominance of missense/nonsense mutations in these genes whereas copy number variations (CNVs) have been seldom described, probably due to the limitations of conventional techniques usually employed for mutational analysis.
In this study we have aimed to analyze the presence of CNVs in some HSCR genes (RET, EDN3, GDNF and ZFHX1B) using the Multiple Ligation-dependent Probe Amplification (MLPA) approach.
Two alterations in the MLPA profiles of RET and EDN3 were detected, but a detailed inspection showed that the decrease in the corresponding dosages were due to point mutations affecting the hybridization probes regions.
Our results indicate that CNVs of the gene coding regions analyzed here are not a common molecular cause of Hirschsprung disease. However, further studies are required to determine the presence of CNVs affecting non-coding regulatory regions, as well as other candidate genes.
先天性巨结肠（HSCR）是一种先天性后肠畸形，是胚胎发育过程中神经嵴细胞迁移中断所致。HSCR 具有复杂的遗传病因，几个基因的突变，主要是原癌基因 RET 的突变，与该疾病有关。这些基因中的错义/无义突变明显占优势，而拷贝数变异（CNVs）则很少被描述，这可能是由于通常用于突变分析的常规技术的局限性所致。
在这项研究中，我们旨在使用多重连接依赖探针扩增（MLPA）方法分析一些 HSCR 基因（RET、EDN3、GDNF 和 ZFHX1B）中的 CNVs 存在情况。
在 RET 和 EDN3 的 MLPA 图谱中检测到两种改变，但详细检查表明，相应剂量的减少是由于影响杂交探针区域的点突变所致。
我们的结果表明，这里分析的基因编码区的 CNVs 不是先天性巨结肠的常见分子病因。然而，需要进一步研究以确定是否存在影响非编码调控区域的 CNVs 以及其他候选基因。
