Genetic analyses of cerebellar malformations

描述（由申请人提供）：人后脑的缺失存在于Joubert综合征和密切相关的小脑-眼-肾综合征以及其他通常分类不佳的小脑畸形疾病中。 虽然这些疾病在临床上是多样的，遗传异质性，他们现在更准确，更可靠地确定通过头颅MRI扫描。 然而，这种畸形的遗传，生物化学和病理生理基础仍然在很大程度上未知。 该项目的目的是确定Joubert综合征，Joubert综合征相关疾病和其他小脑-后脑畸形的基因，以了解小脑的正常发育和功能。 在这个应用程序中，候选人将进行以病人为导向的研究和指导实习生/初级教师，以促进人类小脑畸形的基础研究。 其具体目标是澄清临床特征和频谱的这一复杂的疾病组，通过改进的确认与完善的临床研究，以提高诊断的准确性作为前奏基因识别。 候选人打算通过评价从以下方面提出的候选基因来深入了解这些后脑畸形的分子基础：（i）重叠或等位基因疾病的致病作用;（ii）疾病相关的染色体重排;（iii）利用血缘家系的小脑发育障碍的综合表型和遗传图谱。 通过这些方法，候选人打算推导出潜在的分子病理学和这些疾病的特征之间的逻辑相关性。 鉴定这种畸形的致病基因将为导致后脑畸形的异常小脑发育过程提供深入了解。 此外，结合改进的临床疾病分类学鉴定这些基因将提高生物医学诊断的准确性，为家庭提供精确的复发风险，并可能产生早期产前诊断的选择。 此外，通过这些方法的准确诊断将为纵向临床研究提供基础，提高信息质量，为这些个人及其家庭提供健康护理和管理建议，并最终改善特定治疗的前景。

DESCRIPTION (provided by applicant): Abnormalities of the human hindbrain are present in Joubert syndrome and closely related cerebello-ocular-renal syndromes, and other often poorly classified cerebellar malformation disorders. Although these disorders are clinically diverse and genetically heterogeneous, they are now more accurately and reliably identified by cranial MRI scanning. However, the genetic, biochemical, and pathophysiological bases of such malformations remains largely unknown. The purpose of this project is to identify genes responsible for Joubert syndrome, Joubert syndrome-related disorders, and other cerebellar-hindbrain malformations in order to gain insights into the normal development and function of the cerebellum. In this application, the candidate will undertake patient-oriented research and mentor trainee/junior faculty members to facilitate research into the basis of human cerebellar malformations. The specific objectives are to clarify the clinical features and spectrum of this complex group of disorders by improved ascertainment with refined clinical studies to enhance diagnostic accuracy as a prelude to gene identification. The candidate intends to gain insight into the molecular basis of these hindbrain malformations by evaluating candidate genes suggested from: (i) a causative role for an overlapping or allelic disorder; (ii) disease associated chromosomal rearrangements; (iii) integrated phenotyping and genetic mapping in cerebellar developmental disorders utilizing consanguineous pedigrees. By these means, the candidate intends to derive logical correlations between the underlying molecular pathology and the features of these disorders. Identification of causal genes for such malformations would provide insights into aberrant cerebellar developmental processes, which result in hindbrain malformations. In addition, the identification of such genes in conjunction with improved clinical nosology would enhance the accuracy of biomedical diagnosis, provide precise recurrence risks to families, and potentially generate options for early prenatal diagnosis. Furthermore, accurate diagnosis by these methods would provide the basis for longitudinal clinical studies, improve the quality of information, health care and management recommendations for such individuals and their families and ultimately, improve the prospect for specific therapies.