LINKAGE STUDIES OF WAARDENBURG SYNDROME

多年来，人们已经知道耳聋在家庭中聚集， 这种家族聚集通常是由于遗传疾病。 遗传性耳聋在本质上往往是综合征。 即一个 相关形态学体征和症状的一致性 通过有耳聋倾向的家庭共同隔离。 几次耳聋 综合征似乎是由发挥主要作用的单个基因引起的， 而且很明显是通过显性或隐性方式遗传的， 高反射率的传输。 分子生物学最新进展 联系分析的统计方法现在为我们提供了， 第一次，严格评估这种说法的技术， 生物化学和生理机制的研究进展 潜在的遗传性耳聋 这是一项建议，目的是：（一）确定大量的多路复用 Waardenburg综合征家系，一种通过 具有高等位基因率的常染色体显性主基因座;和ii.）进行 利用丰富的、高度多态的 DNA标记，最近已成为可用的跨越几乎 整个人类基因组 该提案旨在利用资源 通过长期合作， 弗吉尼亚和加劳德特医学院的研究人员和临床医生 大学 这些资源包括广泛的先前经验， 通过手语和电传打字机与聋人社区的成员交流， 终端，提供既定的年度调查工具 适合于识别许多新的家庭，加上广泛的研究， 在实施精确的诊断标准方面的经验， 培养和分子生物学实验室程序， 对大量的高度多态性DNA标记进行基因分型，以及 进行灵敏而强大的统计分析。 标记物的基因分型将首先集中在以前的研究 表明瓦登伯格综合征的基因可能被定位。 几 将对数据采用统计方法，以便充分 利用他们的潜力。 任何强有力的积极调查结果将由 从基因组的主要基因座 Waardenburg综合征的可能性在于， 以便于最终的克隆和测序。

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.