Genetics of Brain Development

无前脑畸形（HPE）是人类大脑和面部最常见的畸形（250个胎儿中有1个，16000个活产婴儿中有1个）。它在遗传上具有极大的异质性，超过80%的HPE基因目前尚不清楚。一般来说，其病因归因于至少12种不同HPE基因的有害突变（或缺失）的新生或常染色体显性遗传。临床上，它表现为不完全外显，其表达性变化很大。HPE的范围从单眼（独眼）和未分裂的前脑，到简单的显微形态，包括孤立的细微面部表现，如单个中央门牙（图1a）。我们在HPE基因鉴定和确认疾病机制方面处于领先地位（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，我们面临着许多挑战。在这里，我们建议将动物模型与传统和最新的基因组工具（靶向捕获，外显子组，全基因组）相结合，以促进我们对HPE的理解。我们过去的努力已经帮助制定了最全面的HPE分子和临床描述。在此过程中，我们在校内外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，并建立了成功的国际合作努力，旨在推动HPE研究和相关条件的未来进展。我们的研究指导了对正常和异常大脑发育的理解。

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.