Familial dysautonomia:: Detection of the IKBKA-P IVS20+6T→C and R696P mutations and frequencies among Ashkenazi Jews
Familial dysautonomia:: Detection of the IKBKA-P IVS20+6T→C and R696P mutations and frequencies among Ashkenazi Jews
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DOI：
10.1002/ajmg.10450
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发表时间：
2002-07-01
期刊：
影响因子：
--
通讯作者：
Desnick, RJ
中科院分区：
文献类型：
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作者：
Dong, JL;Edelmann, L;Desnick, RJ
家族性自主神经异常（FD）是一种常染色体隐性遗传的先天性神经病，几乎只发生在德系犹太人（AJ）人群中。IkappaB激酶复合物相关蛋白（IKBKAP）基因突变导致FD。两个IKBKAP突变，IVS 20（+6T --> C）和R696 P，已确定在FD患者的AJ血统。（6 T--> C）剪接位点突变IVS 20（+）导致> 99.5%的已知FD AJ患者，单倍型分析与共同的创始者一致。相比之下，R696 P突变仅在少数AJ患者中发现。为了便于携带者检测，开发了单一PCR和等位基因特异性寡核苷酸（阿索）杂交测定以便于检测IVS 20（+6T --> C）和R696 P突变。对来自纽约大都市区的2，518名匿名AJ个体的筛查显示，IVS 20（+6 T）（--> C）的携带者频率为1/32（3.2%; 95%CI，2.5-3.9%），与先前基于疾病发病率估计的携带者频率（3.3%）相似。没有发现R696 P病变的携带者，表明该突变在该人群中很罕见（< 1/2，500）。这种敏感和特异性的检测方法应有助于在AJ社区进行FD突变的携带者筛查，以及出生后的诊断测试。(C)2002 Wiley-Liss，Inc.
Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that occurs almost exclusively in the Ashkenazi Jewish (AJ) population. Mutations in the IkappaB kinase complex-associated protein (IKBKAP) gene cause FD. Two IKBKAP mutations, IVS20(+6T --> C) and R696P, have been identified in FD patients of AJ descent. The (6T --> C) splice site mutation IVS20(+) is responsible for > 99.5% of known AJ patients with FD, and haplotype analyses were consistent with a common founder. In contrast, the R696P mutation has been identified in only a few AJ patients. To facilitate carrier detection, a single PCR and allele-specific oligonucleotide (ASO) hybridization assay was developed to facilitate the detection of both the IVS20(+6T --> C) and R696P mutations. Screening of 2,518 anonymous AJ individuals from the New York metropolitan area revealed a carrier frequency for IVS20(+6T) (--> C) of 1 in 32 (3.2%; 95% CI, 2.5-3.9%), similar to the previously estimated carrier frequency (3.3%) based on disease incidence. No carrier was identified for the R696P lesion, indicating that the mutation was rare in this population (< 1 in 2,500). This sensitive and specific assay should facilitate carrier screening for FD mutations in the AJ community, as well as postnatal diagnostic testing. (C) 2002 Wiley-Liss, Inc.