The Genetic Basis of Mid-Hindbrain Malformations

描述（由申请人提供）：与其他类型的脑畸形相比，脑干和小脑畸形是人类发育障碍的一种相对常见的原因（至少每1000个新生儿中有0.24个）。其中最著名和最常见的是ddy - walker畸形（DWM），但它经常与孤立性小脑蚓部发育不全（CVH）和磨牙畸形（MTM）相混淆，见于Joubert综合征和相关疾病。在这里，我们提出了一个综合的方法来综合征描述和基因鉴定这3个重叠的畸形。我们把它们放在一起研究，因为大多数临床医生难以区分它们，我们迄今为止的经验表明，DWM和MTM的轻度变异可能很难或不可能与孤立的CVH区分开来。我们的初步研究使我们对这些疾病的理解取得了重大进展，包括有用的临床描述，结合至少4个潜在重要致病基因的鉴定和其他几个致病基因的物理定位。具体来说，我们发现了CVH (OPHN1), DWM （ZIC1和ZIC4）和MTM （AHI1和NPHP1）的第一个致病基因，并将DWM的其他致病基因定位在染色体6p25上，MTM的其他致病基因定位在染色体7和13上。我们已经确定了足够的受试者，以允许鉴定6p25 DWM基因，并绘制其他后脑畸形基因。我们在基因型-表型分析方面的经验将使进展迅速转化为临床有用性。总的来说，我们相信对这些畸形及其致病基因的深入研究是非常及时的，这将促进人们对大脑发育的了解，并有助于对受这些疾病影响的个人和家庭的诊断和医疗护理。

DESCRIPTION (provided by applicant): Malformations of the brainstem and cerebellum are collectively a relatively common (at least 0.24 per 1000 births) cause of developmental disabilities in humans that have been understudied compared to other types of brain malformations. The best known and most common of these is Dandy-Walker malformation (DWM), but this is often confused with isolated cerebellar vermis hypoplasia (CVH) and the molar tooth malformation (MTM) seen in Joubert syndrome and related disorders. Here we propose a comprehensive approach to syndrome delineation and gene identification for these 3 overlapping malformations. We approach them together as most clinicians have difficulty distinguishing between them, and our experience to date suggests that mild variants of DWM and MTM may be very difficult or impossible to distinguish from isolated CVH. Our preliminary studies have resulted in significant progress in our understanding of these disorders, and include useful clinical delineation combined with identification of at least 4 potentially important causative genes and physical mapping of several more. Specifically, we have found the first causative genes for CVH (OPHN1), DWM (ZIC1 and ZIC4) and MTM (AHI1 and NPHP1), and mapped additional causative genes for DWM to chromosome 6p25 and for MTM to chromosomes 7 and 13. We have already ascertained sufficient subjects for to allow identification of the 6p25 DWM gene, and to map additional hindbrain malformation genes. Our experience with genotype-phenotype analysis will allow progress to be quickly translated to clinical usefulness. Overall, we believe that intensive studies of these malformations and their causative genes are very timely, and will advance knowledge regarding brain development in general, and contribute to the diagnosis and medical care of the individuals and families affected by these disorders.