Genetics of Brain Development

无前脑畸形(HPE)是人类最常见的大脑和面部畸形(每250个胎儿中有1个，每16,000个活产婴儿中就有1个)。它具有高度的遗传异质性，80%以上的HPE基因目前尚不清楚。一般说来，其病因可归因于至少12种不同HPE基因的有害突变(或缺失)的从头遗传或常染色体显性遗传。临床上，它表现为不完全外显，其表现力极不稳定。HPE的范围从单眼(单眼)和未分割的前脑，在一个极端，到简单的微型体，由孤立的微妙面部表现，如单个中央切牙(图1a)我们在HPE基因识别和确认疾病机制方面一直处于领先地位(图1b)。然而，尽管取得了这些进展，其病因、发病机制以及对这种变异的潜在遗传和环境来源的任何解释都是不完整的。因此，未来将面临许多挑战。在这里，我们建议使用动物模型结合传统的和最新的基因组工具(靶向捕获、外显子组、全基因组)来促进我们对HPE的理解。我们过去的努力帮助制定了最全面的HPE分子和临床描述。为此，我们在院内和院外的科学家和临床医生之间进行了协同努力，制定了不断发展的诊断标准，并成功地建立了国际合作努力，旨在促进HPE研究和相关疾病的未来进展。我们的研究指导了对正常和异常大脑发育的理解。 我们成功的最佳总结可以在我们的Amer J Med Genet问题154C中找到，该问题专门针对HPE。这一问题表明，我们坚持多学科、多中心的方法来描述HPE的临床/分子谱以及与单个基因的基因-表型关联。我们的方法旨在通过使用细胞遗传学分析、拷贝数变异分析、突变分析、特定诊断算法以及当前和下一代基因组学策略来寻找关联基因来揭示HPE的分子基础。我们过去和未来的目标包括决心调动NIH社区和校外科学家的资源，对在我们的先证者中检测到的突变进行功能研究。虽然这通常是昂贵和耗时的，但我们认为这是我们对参与其中的家庭的主要责任之一。

Holoprosencephaly (HPE) is the most common malformation of the brain and face in humans (1 in 250 fetuses, and 1/16,000 live births). It is extremely genetically heterogeneous with over 80% of HPE genes presently unknown. Generally, its etiology is attributed to either de novo or autosomal dominant inheritance of deleterious mutations (or deletions) of at least a dozen different HPE genes. Clinically, it displays incomplete penetrance, and its expressivity is extremely variable. HPE can range from a single eye (cyclopia) and un-divided forebrain, at one extreme, to simple microforms, consisting of isolated subtle facial manifestations such as a single central incisor (Figure 1a) We have been leaders in the identification of HPE genes and confirming disease mechanisms (Figure 1b). However, despite these advances, its etiology, pathogenesis and any explanations for the underlying genetic and environmental sources of this variability are incomplete. Therefore, there are many challenges ahead. Here we propose to use animal models in concert with conventional and the latest in genomic tools (targeted capture, exome, whole genome) to advance our understanding of HPE. Our past efforts have helped formulate the most comprehensive molecular and clinical descriptions of HPE. In doing so, weve synergized efforts between intramural and extramural scientists and clinicians, set evolving diagnostic standards, and established successful international collaborative efforts aimed at future progress in HPE research and related conditions. Our studies guide an understanding of both normal and abnormal brain development. The best summary of our successes can be found in our Amer J Med Genet issue 154C, which is devoted exclusively to HPE. This issue illustrates our insistence on a multi-disciplinary, multi-center approach to the description of the clinical/molecular spectrum of HPE and the genotype-phenotype associations with individual genes. Our approach aims to uncover the molecular basis of HPE through a search for associative genes using cytogenetic analysis, copy number variation analysis, mutational analysis, specific diagnostic algorithms, in conjunction with present and next generation genomics strategies. Our past and future goals include the determination to marshal the resources of the NIH community and extramural scientists to perform functional studies on the mutations detected among our probands. Although often expensive and time consuming, we consider this one of our primary responsibilities to a family that participates.