Yang Ren-Qiang, Jabbari Javad, Cheng Xiao-Shu, Jabbari Reza, Nielsen Jonas B, Risgaard Bjarke, Chen Xu, Sajadieh Ahmad, Haunsø Stig, Svendsen Jesper Hastrup, Olesen Morten S, Tfelt-Hansen Jacob
Laboratory of Molecular Cardiology, Department of Cardiology, the Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
BMC Genet. 2014 Jun 18;15:74. doi: 10.1186/1471-2156-15-74.
Marfan syndrome (MFS) is a rare autosomal dominantly inherited connective tissue disorder with an estimated prevalence of 1:5,000. More than 1000 variants have been previously reported to be associated with MFS. However, the disease-causing effect of these variants may be questionable as many of the original studies used low number of controls. To study whether there are possible false-positive variants associated with MFS, four in silico prediction tools (SIFT, Polyphen-2, Grantham score, and conservation across species) were used to predict the pathogenicity of these variant.
Twenty-three out of 891 previously MFS-associated variants were identified in the ESP. These variants were distributed on 100 heterozygote carriers in 6494 screened individuals. This corresponds to a genotype prevalence of 1:65 for MFS. Using a more conservative approach (cutoff value of >2 carriers in the EPS), 10 variants affected a total of 82 individuals. This gives a genotype prevalence of 1:79 (82:6494) in the ESP. A significantly higher frequency of MFS-associated variants not present in the ESP were predicted to be pathogenic with the agreement of ≥3 prediction tools, compared to the variants present in the ESP (p = 3.5 × 10-15).
This study showed a higher genotype prevalence of MFS than expected from the phenotype prevalence in the general population. The high genotype prevalence suggests that these variants are not the monogenic cause of MFS. Therefore, caution should be taken with regard to disease stratification based on these previously reported MFS-associated variants.
马凡综合征（MFS）是一种罕见的常染色体显性遗传结缔组织疾病，估计患病率为1:5000。此前已报道1000多个变异与MFS相关。然而，由于许多原始研究使用的对照数量较少，这些变异的致病作用可能存在疑问。为了研究是否存在与MFS相关的可能的假阳性变异，使用了四种计算机预测工具（SIFT、Polyphen-2、格兰瑟姆评分和跨物种保守性）来预测这些变异的致病性。
在ESP中鉴定出891个先前与MFS相关的变异中的23个。这些变异分布在6494名筛查个体中的100名杂合子携带者中。这对应于MFS的基因型患病率为1:65。使用更保守的方法（EPS中>2名携带者的临界值），10个变异共影响82名个体。这在ESP中给出了1:79（82:6494）的基因型患病率。与ESP中存在的变异相比，在ESP中不存在的与MFS相关的变异被预测为致病性的频率显著更高，且有≥3种预测工具达成一致（p = 3.5×10-15）。
本研究显示MFS的基因型患病率高于一般人群中表型患病率的预期。高基因型患病率表明这些变异不是MFS的单基因病因。因此，对于基于这些先前报道的与MFS相关的变异进行疾病分层应谨慎。
