LINKAGE STUDIES OF WAARDENBURG SYNDROME

多年来，人们已经知道耳聋会聚集在家庭中，而且 这种家族聚集性通常是由遗传疾病引起的。 遗传性耳聋在本质上通常是综合征性的。也就是说，一个 相关的形态体征和症状的一致谱系 通过对耳聋有责任的家庭进行共同隔离。几种耳聋 综合症似乎是由发挥重大影响的单个基因引起的， 显然是通过显性或隐性的方式遗传的 高清晰度的传输。分子生物学的最新进展 而连锁分析的统计方法现在为我们提供了 第一次，使用严格评估这一主张的技术，并 生化和生理机制的研究进展 潜在的遗传性耳聋。 这是一项建议：i.)确定了大量的多厅 瓦登堡综合征家系，一种遗传性耳聋 高外显性的常染色体显性主基因座；进行，进行 利用丰富、高度多态的分子标记对这些家系进行连锁分析 最近出现的DNA标记几乎可以跨越 整个人类基因组。这项提议寻求利用资源 通过两家公司之间的长期合作提供独特的 弗吉尼亚和加拉德特医学院的研究人员和临床医生 大学。这些资源包括丰富的沟通经验。 通过手语和电传打字与聋人社区成员联系 码头、现有的年度调查仪器的可用性 适合识别许多新的家族，再加上广泛的研究 实施准确的诊断标准，指导细胞的经验 培养和分子生物学实验室所需的程序 对大量高度多态的DNA标记进行基因分型，以及 进行敏感而有力的统计分析。 标记的基因分型将首先集中在以前研究的领域 提示瓦登堡综合征的一个基因可能存在。几个 将对数据采用统计方法，以便充分 利用他们的潜力。任何强有力的积极发现都将由 从基因组中主位点处的那部分克隆额外的标记 因为瓦登堡综合症可能是为了更好地定位它 正是为了方便最终的克隆和测序。

It has been known for many years that deafness aggregates in families, and that this familial aggregation is often due to a genetic disorder. Genetically based deafness is often syndromic in nature. That is, a consistent repertoire of associated morphological signs and symptoms cosegregates through families with liability to deafness. Several deafness syndromes appear to be caused by single genes that exert a major effect, and that are clearly inherited via either dominant or recessive modes of transmission with high penetrance. Recent advances in molecular biology and statistical approaches to linkage analysis now provide us, for the first time, with the techniques to rigorously evaluate this claim, and to progress towards understanding the biochemical ad physiological mechanisms underlying genetically transmitted forms of deafness. This is a proposal to: i.) ascertain a large number of multiplex Waardenburg syndrome pedigrees, a type of genetic deafness transmitted via an autosomal dominant major locus with high penetrance; and ii.) to conduct linkage analyses on these pedigrees using the abundant, highly polymorphic DNA markers that have recently become available to span virtually the entire human genome. The proposal seeks to capitalize on resources uniquely available through the longstanding collaboration between researchers and clinicians at the Medical College of Virginia and Gallaudet University. These resources include broad prior experience communicating with members of the deaf community via sign language and teletype terminals, the availability of an established annual survey instrument suitable for identifying many new families, coupled with extensive research experience in implementing precise diagnostic criteria, conducting the cell culture and molecular biological laboratory procedures necessary to genotype a very large number of highly polymorphic DNA markers, and performing sensitive and powerful statistical analyses. Genotyping of markers will first focus on areas where previous studies suggest a gene for Waardenburg syndrome might be located. Several statistical approaches will be applied to the data in order to fully utilize their potential. Any strong positive findings will be pursued by cloning additional markers from that part of the genome where a major locus for Waardenburg syndrome might lie in order to map its location more precisely to facilitate its eventual cloning and sequencing.