A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population.
A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population.
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DOI：
10.1186/1471-2350-13-72
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发表时间：
2012-08-15
影响因子：
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通讯作者：
Braverman NE
中科院分区：
文献类型：
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作者：
Levesque S;Morin C;Guay SP;Villeneuve J;Marquis P;Yik WY;Jiralerspong S;Bouchard L;Steinberg S;Hacia JG;Dewar K;Braverman NE
齐薇格综合征(Zellweger综合征，ZS)是一种由13个PEX基因中的任何一个基因突变引起的过氧化物酶体生物发生障碍。魁北克省萨盖奈-拉克-圣让地区(SLSJ)的法裔加拿大人怀疑ZS的发病率增加，但这一问题仍未解决。我们从1990-2010年间诊断为过氧酶体功能障碍的SLSJ中确定了5名ZS患者，并使用下一代测序(NGS)对其中一名患者的已知PEX基因的所有编码外显子进行了测序以用于诊断确认。在另4例患者中发现了PEX6纯合子突变(c.802_815del，p.[Val207_Gln294del，Val76_Gln294del])。亲本杂合性总体上得到了证实。ZS的发病率估计为每12,191名活产儿中有1名，携带者频率为1/55。此外，我们提供的数据表明，该突变取消了SF2/ASF剪接增强子结合位点，导致使用了两个可供选择的隐蔽供体剪接位点，并预测编码一个内部删除的框内蛋白。我们报告了由PEX6创始人突变引起的法裔加拿大人SLSJ中ZS发生率的增加。据我们所知，这是全球报告的ZS发病率最高的一次。这些发现对携带者筛查有意义，并支持NGS用于过氧化体疾病的分子确认。
Zellweger syndrome (ZS) is a peroxisome biogenesis disorder due to mutations in any one of 13 PEX genes. Increased incidence of ZS has been suspected in French-Canadians of the Saguenay-Lac-St-Jean region (SLSJ) of Quebec, but this remains unsolved. We identified 5 ZS patients from SLSJ diagnosed by peroxisome dysfunction between 1990–2010 and sequenced all coding exons of known PEX genes in one patient using Next Generation Sequencing (NGS) for diagnostic confirmation. A homozygous mutation (c.802_815del, p.[Val207_Gln294del, Val76_Gln294del]) in PEX6 was identified and then shown in 4 other patients. Parental heterozygosity was confirmed in all. Incidence of ZS was estimated to 1 in 12,191 live births, with a carrier frequency of 1 in 55. In addition, we present data suggesting that this mutation abolishes a SF2/ASF splice enhancer binding site, resulting in the use of two alternative cryptic donor splice sites and predicted to encode an internally deleted in-frame protein. We report increased incidence of ZS in French-Canadians of SLSJ caused by a PEX6 founder mutation. To our knowledge, this is the highest reported incidence of ZS worldwide. These findings have implications for carrier screening and support the utility of NGS for molecular confirmation of peroxisomal disorders.