DEAFNESS IN WS1: SEARCH FOR GENETIC MODIFIERS

作为一名儿科遗传学家，私家侦探对 了解遗传性疾病的分子病理学，尤其是 在孩子们身上。长期目标是在学术领域建立自己的事业 医学，这将使PI能够研究修饰剂的重要性 临床相关遗传性疾病的表型变异基因。 目前的部门项目与这项建议高度相关， 将为私家侦探的职业生涯提供必要的基石 发展。听力损失影响到至少5%的人口 出生时或出生后早期严重耳聋的发生率 据估计，每1000名儿童中约有0.8名儿童。这是病因学上的 异质性，遗传因素占所有病例的一半 深度耳聋，其中10%-20%是由于特定的 遗传性综合症。瓦登堡综合征(WS)是一种症状综合体 包括耳聋、角质异常症、白额和 异色症。我们参与了将该基因定位到2q35区域， 在WS中发现遗传异质性，并在示范中 PAX3基因座的突变异质性。广泛的表型 在WS1家系内观察到的变异与显著的 MZ双胞胎的表型一致性强烈表明修饰物 基因(S)促成了这种可变性。本条例草案建议 鉴定和鉴定导致个体耳聋的基因(S) 他们遗传了WS 1型的基因。我们已经鉴定出22个WS1 至少有两个或更多WS1兄弟姐妹且均受影响的家庭 耳聋。这是一个理想的定位修饰基因(S)的方法 “感情用事”只有一种做法。两层映射策略，涉及 建议先进行候选基因搜索，然后进行全基因组扫描。 除了使用非参数分析方法外，还将使用 提取最大信息量的传统参数方法 正在研究的家庭。我们还将进一步描述光谱的特征 30个WS1家系中PAX3基因突变的研究 与修饰基因的潜在相互作用(S)。成功者 WS中导致耳聋的修饰基因的鉴定可能导致 到改进的预测测试。

As a pediatric geneticist, the P.I. has a keen interest in understanding the molecular pathology of inherited disorders, especially in children. The long term goal is to establish a career in academic medicine, which would allow the PI to study the importance of modifier genes for phenotypic variation in clinically relevant genetic disorders. Current Departmental projects are highly relevant to this proposal and will provide the necessary building blocks for the PI's career development. Hearing loss affects at least 5 percent of the population with the incidence of profound deafness at birth or during early childhood being estimated as about 0.8 per 1000. It is etiologically heterogenous, with genetic factors accounting for half of all cases of profound deafness, 10-20 percent of which are due to a specific hereditary syndrome. Waardenburg syndrome (WS) is a symptom complex that includes deafness, dystopia canthorum, white forelock and heterochromia. We participated in mapping the gene to 2q35 region, the discovery of genetic heterogeneity in WS, and in the demonstration of mutational heterogeneity at the PAX3 locus. The extensive phenotypic variation observed within WS1 families combined with the striking concordance for phenotype in MZ twins strongly suggests that modifier gene(s) contribute to this variability. The present proposes to identify and characterize the gene(s) causing deafness in individuals who have inherited a gene for WS type 1. We have identified 22 WS1 families with a minimum of 2 or more WS1 siblings who are both affected with deafness. This is ideal for mapping modifier gene(s) by an "affecteds" only approach. A two tiered mapping strategy involving a candidate gene search followed by a genome wide scan is proposed. Nonparametric methods of analysis will be used in addition to the traditional parametric approach to extract maximum information from families being studies. We will also further characterize the spectrum of PAX3 mutations in 30 available families with WS1 and study their potential interaction with the modifier gene(s). The successful identification of modifier genes which cause deafness in WS could lead to improved predictive testing.