Genetic Analysis of Microcephaly in Tunisian Population

描述（由申请人提供）：小头畸形是指人类大脑无法达到正常大小的一种情况。它与智力迟钝、发育迟缓、神经运动障碍和癫痫有关。因此，它是儿童神经残疾的主要原因。小头畸形的病因多种多样，但许多小头畸形综合征是常染色体隐性遗传的。因此，遗传性小头畸形在近亲婚姻常见的国家和地区尤为普遍。突尼斯就是这样一个国家，因为近亲结婚的比例估计为33%。突尼斯人口的大多数是阿拉伯人，但突尼斯的基因组成在阿拉伯国家中是独一无二的，因为它长期以来一直是东西方之间以及欧洲、非洲和亚洲之间的十字路口。因此，通过研究突尼斯人群中的遗传性小头畸形，我们可能会发现小头畸形的新遗传原因。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，我们将能够通过开发改进的遗传诊断和咨询来使受影响的个人及其家庭受益。这项工作将与突尼斯Charles Nicolle医院的遗传学系合作进行，该医院是该国最大的遗传学中心。我们将通过临床招募常染色体隐性小头畸形患者和家系，并利用最先进的高密度SNP全基因组筛查的纯合性作图方法对患者进行遗传分析。该项目的主要目标之一是发展Charles Nicolle医院的遗传研究能力，大部分工作将在我们美国公共卫生相关小组的协助下进行：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，是儿童神经系统残疾的主要原因。它更常见于亲属之间婚姻常见的国家和地区，如突尼斯，但在包括美国在内的任何地方都可以看到突尼斯独特的人口结构允许识别新的小头畸形基因，一旦发现致病基因，美国的小头畸形儿童及其家庭也受益于基于DNA的诊断测试。因此，我们的工作结果将有助于改善这组毁灭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.