A genetic study of Wilson's disease in the United Kingdom
A genetic study of Wilson's disease in the United Kingdom
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DOI：
10.1093/brain/awt035
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发表时间：
2013-05-01
期刊：
影响因子：
14.5
通讯作者：
Bandmann, Oliver
中科院分区：
文献类型：
--
作者：
Coffey, Alison J.;Durkie, Miranda;Bandmann, Oliver
以前的研究未能在大量临床诊断病例中识别Wilson病基因ATP 7 B的突变。这导致了对这种情况的遗传异质性的担忧，但也表明存在不寻常的突变机制。现在，我们提出了我们的研究结果，在181例来自英国的临床和生化证实威尔逊病。共检测到116种不同的ATP 7 B突变，其中32种是新的。总体突变检测频率为98%。因此，导致威尔逊病表型的基因突变而不是ATP 7 B的可能性非常低。我们报告的第一例威尔逊病由于节段性单亲isodisomy以及三个患者与三个ATP 7 B突变和三个家庭与威尔逊病在连续两代。我们通过对1000名对照受试者的ATP 7 B的整个编码区和相邻剪接位点进行测序，确定了英国威尔逊病的遗传患病率。如果分析中仅包括先前报告为Wilson病患者突变的单核苷酸变异（2类变异），则具有致病性计算机模拟证据的所有单核苷酸变异（1类变异）的频率为0.056或0.040。因此，杂合子、推定或确定的疾病相关的ATP 7 B突变的频率显著高于先前报道的一般人群中杂合子ATP 7 B突变携带者1：90（或0.011）的发生率（1类变异体P < 2.2 x 10（-16）或仅2类变异体P < 5 x 10（-11））。随后排除了4种2类变体，没有额外的致病性计算机模拟证据，导致突变频率进一步降低至0.024。使用这种最保守的方法，预测携带两个突变致病性ATP 7 B等位基因的个体的计算频率为1：7026，因此仍然显著高于通常报道的Wilson病的患病率1：30 000（P = 0.00093）。我们的研究为Wilson病的单基因遗传提供了强有力的证据。这也对临床实践中的ATP 7 B分析有重要意义，即需要考虑不寻常的遗传机制，如单亲二体性或可能存在的三个ATP 7 B突变。威尔逊病的遗传患病率和临床诊断病例数之间的显著差异可能是由于ATP 7 B突变的突变率降低和未能诊断出患有这种显著可治疗疾病的患者。
Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson's disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson's disease phenotype is therefore very low. We report the first cases with Wilson's disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson's disease in two consecutive generations. We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson's disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 x 10(-16) for Class 1 variants or P < 5 x 10(-11) for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson's disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson's disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson's disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.