A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population

BMC Medical Genetics

Nancy E Braverman⁵  Ken Dewar³  Joseph G Hacia⁶  Steven Steinberg⁷  Luigi Bouchard²  Sarn Jiralerspong⁵  Wing Yan Yik⁶  Pascale Marquis³  Josee Villeneuve⁴  Simon-Pierre Guay²  Charles Morin⁴  Sebastien Levesque¹ 

[1] Department of Pediatrics, Centre Hospitalier Universitaire de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, QC, J1H 5N4, Canada;ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, Canada;McGill University and Genome Quebec Innovation Center, Montreal, Canada;Department of Pediatrics, Chicoutimi Hospital, Saguenay, Canada;Department of Human Genetics, McGill University, Montreal, Canada;Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, USA;Department of Neurogenetics, Kennedy-Krieger Institute, Baltimore, USA

关键词: Next generation sequencing;    Peroxisome biogenesis disorders;    Founder effect;    Zellweger syndrome;   

Others  :  1177813
DOI  :  10.1186/1471-2350-13-72

 received in 2012-05-20, accepted in 2012-08-08,  发布年份 2012

【 摘 要 】

Background

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.

Methods

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.

Results

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.

Conclusion

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.

【 授权许可】

   
2012 Levesque et al.; licensee BioMed Central Ltd.

【 图 表 】

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