Canavan disease: Carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay
Canavan disease: Carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay
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DOI：
10.1002/ajmg.a.20334
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发表时间：
2004-01-15
影响因子：
2
通讯作者：
Stockley, TL
中科院分区：
文献类型：
--
作者：
Feigenbaum, A;Moore, R;Stockley, TL
卡纳万病（CD）是一种常染色体隐性进行性神经退行性疾病，常见于德系犹太人（AJ）人群。在AJ人群中，导致乳糜泻的最常见突变的携带率通常为1:37-1:40。我们发现在过去20年里，多伦多16万人口中只有两例乳糜泻确诊病例，估计出生率为每年1500 - 2000人，这并不支持这一观点。因此，我们开展了一项流行横断面筛查研究，以确定该人群中CD的携带者率。为了使用分子技术对CD进行低成本、高通量的群体检测，我们首先开发了一种新的分子检测方法，使用多重荧光等位基因特异性聚合酶链反应（PCR）来检测AJ群体中导致CD的三种最常见突变（A854C、C693A、C914A）和C693A突变位点的中性多态性。在测试过程中，我们注意到携带A854C突变的个体在C693A突变位点（Y231X）也有T多态性。我们证实，在所有A854C携带者中，854C突变与693T多态性处于不平衡状态，表明AJ群体中存在A854C突变的创始染色体。从1423个样本中发现了25个携带者，其携带率为1:57，与广泛引用的1:40不同，支持我们观察到的疾病频率。(C) 2003 Wiley-Liss, Inc。
Canavan disease (CD) is an autosomal recessive progressive neurodegenerative disorder prevalent in the Ashkenazi Jewish (AJ) population. The carrier rate for the most common mutations that cause CD in the AJ population is often quoted as 1:37-1:40. This is not supported by our finding of only two diagnosed cases of CD in the last 20 years in the Toronto AJ population of 160,000 and an estimated birth rate of 1,500-2,000 per year. Therefore, we embarked on a prevalence cross-sectional screening study to determine the carrier rate of CD in this population. In order to perform low-cost, high-throughput population testing for CD using molecular techniques, we first developed a novel molecular assay using multiplex fluorescent allele specific polymerase chain reaction (PCR) to test for the three most common mutations causing CD in the AJ population (A854C, C693A, C914A) and a neutral polymorphism at the site of the C693A mutation. During testing it was noted that individuals who were carriers of the A854C mutation also had a T polymorphism at the site of the C693A mutation (Y231X). We confirmed that in all A854C carriers the 854C mutation was in disequilibrium with the 693T polymorphism, indicating a founder chromosome for the A854C mutation in the AJ population. Twenty-five carriers were found from 1,423 samples yielding a carrier rate of 1:57, differing from the widely quoted frequency of 1:40 and supporting our observed frequency of disease. (C) 2003 Wiley-Liss, Inc.