Department of Pediatrics, Université de Sherbrooke, Sherbrooke, Canada.
BMC Med Genet. 2012 Aug 15;13:72. doi: 10.1186/1471-2350-13-72.
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.
泽尔韦格综合征（ZS）是一种过氧化物酶体生物发生障碍，由 13 个 PEX 基因中的任何一个突变引起。魁北克萨格奈-拉克圣让地区（SLSJ）的法裔加拿大人中，ZS 的发病率增加已被怀疑，但这仍未得到解决。
我们在 1990 年至 2010 年间通过过氧化物酶体功能障碍诊断出 5 名来自 SLSJ 的 ZS 患者，并在一名患者中使用下一代测序（NGS）对已知 PEX 基因的所有编码外显子进行测序，以进行诊断确认。
在 PEX6 中发现了一个纯合突变（c.802_815del，p.[Val207_Gln294del，Val76_Gln294del]），随后在其他 4 名患者中也发现了该突变。所有患者的父母均为杂合子。ZS 的发病率估计为每 12191 例活产儿中 1 例，携带者频率为每 55 例 1 例。此外，我们还提供了数据表明，该突变消除了 SF2/ASF 剪接增强子结合位点，导致使用两个替代隐性供体位点，并预测编码一个内部缺失的框内蛋白。
我们报告了 SLSJ 的法裔加拿大人中 ZS 的发病率增加，由 PEX6 启动子突变引起。据我们所知，这是全球报道的 ZS 发病率最高的一次。这些发现对携带者筛查具有重要意义，并支持 NGS 用于过氧化物酶体疾病的分子确认。
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