New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases
New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases
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DOI：
10.1136/jmedgenet-2011-100339
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发表时间：
2011-11-01
影响因子：
4
通讯作者：
Odent, Sylvie
中科院分区：
文献类型：
--
作者：
Mercier, Sandra;Dubourg, Christele;Odent, Sylvie
前脑无裂畸形（HPE）是人类最常见的前脑缺陷。方法对645例HPE先证者（699名亲属），包括51%的胎儿和49%的活产儿，进行了一个大型的欧洲系列研究。SHH、SIX 3和TGIF突变在这些病例中超过70%是遗传的，而ZIC 2中70%的突变是从头发生的。此外，22%的260例患者通过阵列比较基因组杂交筛选检测到重排。15个先证者有两个突变，为HPE中的“多次击中过程”提供了额外的支持。SHH、SIX 3和TGIF的脑畸形严重程度与面部特征呈正相关，但ZIC 2突变没有发现这种相关性。最严重的HPE类型与SIX 3和ZIC 2突变相关，而微小型与SHH突变相关。该研究的重点是相关的脑畸形，包括神经元迁移缺陷，这在ZIC 2突变的个体中占主导地位，以及神经管缺陷，这通常与ZIC 2（脊柱裂）和TGIF突变有关。27%的HPE患者存在颅面外特征（ZIC 2突变者高达40%），肾/泌尿系统缺陷与SHH和ZIC 2突变之间存在显著相关性。结论基于这些新的表型-基因型相关性，提出了一种算法，以便于HPE的分子分析和遗传咨询。
Background Holoprosencephaly (HPE) is the most common forebrain defect in humans. It results from incomplete midline cleavage of the prosencephalon.Methods A large European series of 645 HPE probands (and 699 relatives), consisting of 51% fetuses and 49% liveborn children, is reported.Results Mutations in the four main genes involved in HPE (SHH, ZIC2, SIX3, TGIF) were identified in 25% of cases. The SHH, SIX3, and TGIF mutations were inherited in more than 70% of these cases, whereas 70% of the mutations in ZIC2 occurred de novo. Moreover, rearrangements were detected in 22% of the 260 patients screened by array comparative genomic hybridisation. 15 probands had two mutations providing additional support for the 'multiple-hit process' in HPE. There was a positive correlation between the severity of the brain malformation and facial features for SHH, SIX3, and TGIF, but no such correlation was found for ZIC2 mutations. The most severe HPE types were associated with SIX3 and ZIC2 mutations, whereas microforms were associated with SHH mutations. The study focused on the associated brain malformations, including neuronal migration defects, which predominated in individuals with ZIC2 mutations, and neural tube defects, which were frequently associated with ZIC2 (rachischisis) and TGIF mutations. Extracraniofacial features were observed in 27% of the individuals in this series (up to 40% of those with ZIC2 mutations) and a significant correlation was found between renal/urinary defects and mutations of SHH and ZIC2.Conclusions An algorithm is proposed based on these new phenotype-genotype correlations, to facilitate molecular analysis and genetic counselling for HPE.