Genetic Analysis of Microcephaly in Tunisian Population

描述(申请人提供)：小头畸形是指人脑无法达到正常大小的情况。它与智力低下、发育迟缓、神经运动障碍和癫痫有关。因此，它是导致儿童神经功能障碍的一个主要原因。小头畸形的原因是多种多样的，但许多小头畸形综合征是以常染色体隐性遗传的形式遗传的。因此，遗传性小头畸形症在近亲婚姻普遍存在的国家和地区尤为普遍。突尼斯就是这样一个国家，据估计，突尼斯近亲婚姻的比例为33%。突尼斯人口的大部分是阿拉伯人，但突尼斯的基因构成在阿拉伯国家中是独一无二的，因为它作为东西方以及欧洲、非洲和亚洲之间的十字路口的历史角色由来已久。因此，通过对突尼斯人群遗传性小头畸形症的研究，我们有可能确定小头畸形症的新的遗传原因。此外，通过对突尼斯遗传性小头畸形综合征的遗传流行病学分析，我们将能够通过改进遗传诊断和咨询，使受影响的个人及其家庭受益。这项工作将与突尼斯最大的遗传学中心--突尼斯查尔斯·尼科尔医院的遗传科合作进行。我们将通过临床登记常染色体隐性小头畸形症患者和家系，并利用最先进的高密度SNP全基因组筛查的纯合子作图方法对患者进行基因分析。该项目的主要目标之一是发展Charles Nicolle医院的基因研究能力，在我们美国公共卫生小组的协助下，将在那里开展大部分工作。与公共卫生相关：遗传性小头畸形是一组人类大脑无法达到正常大小的疾病，是儿童神经功能障碍的主要原因。小头畸形症更多见于亲属结婚普遍的国家和地区，如突尼斯，但在包括美国在内的所有国家和地区都很常见。突尼斯独特的人口结构允许识别新的小头畸形症基因，一旦发现致病基因，美国小头畸形症儿童及其家人也将受益于基于DNA的诊断测试。因此，我们的工作结果将有助于改善这一组破坏性疾病的遗传诊断和遗传咨询，并通过解开大脑发育的基本机制，希望为最终治疗这种和其他神经发育障碍铺平道路。

DESCRIPTION (provided by applicant): Microcephaly refers to a condition in which the human brain fails to achieve normal size. It is associated with mental retardation, developmental delay, neuromotor disability, and epilepsy. Therefore, it is a major cause of neurological disability in children. The causes of microcephaly are diverse, but many microcephaly syndromes are inherited as autosomal recessive conditions. Thus, genetic microcephaly is particularly prevalent in countries and regions where consanguineous marriages are common. Tunisia is one such country, as the proportion of consanguineous marriages in Tunisia is estimated as 33%. The majority of the Tunisian population is made up of Arabs, but the genetic make up of Tunisia is unique among the Arab countries because of its long historical role as a crossroad between East and West, and among Europe, Africa and Asia. Therefore, by studying genetic microcephaly in the Tunisian population, we are likely to identify novel genetic causes of microcephaly. In addition, through the genetic epidemiological analysis of genetic microcephaly syndromes in Tunisia, we will be able to benefit the affected individuals and their families by developing improved genetic diagnosis and counseling. This work will be performed in collaboration with the Department of Genetics at Hospital Charles Nicolle in Tunis, which is the largest genetics center in the country. We will enroll the patients and families with autosomal recessive microcephaly through their clinic, and perform genetic analysis of the patients by utilizing the method of homozygosity mapping with state-of-the-art high density SNP genome-wide screening. One of the major goals of this project is to develop genetic research capacity at Hospital Charles Nicolle, and a large part of work will be carried out there, with assistance from our group in the U.S. PUBLIC HEALTH RELEVANCE: Genetic microcephaly is a group of disorders in which the human brain fails to achieve normal size, and is a major cause of neurological disability in children. It is more commonly seen in countries and regions where marriages between relatives are common, such as Tunisia, but is seen everywhere including the U.S. The unique population structure of Tunisia allows the identification of novel microcephaly genes, and once the causative genes are found, children with microcephaly and their families in the U.S. also benefit from DNA-based diagnostic testing. Thus, the results of our work will help improve the genetic diagnosis and genetic counseling of this group of devastating disorders, and by unraveling the basic mechanisms of brain development, it is hoped to pave the way toward eventual treatment of this and other neurodevelopmental disorders.