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

BMC Medical Genetics

Research Article

Wing Yan Yik¹  Joseph G Hacia¹  Luigi Bouchard²  Simon-Pierre Guay²  Nancy E Braverman³  Sarn Jiralerspong³  Ken Dewar⁴  Steven Steinberg⁵  Josee Villeneuve⁶  Sebastien Levesque⁷  Charles Morin⁸  Pascale Marquis⁹ 

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

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

DOI  :  10.1186/1471-2350-13-72

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

来源: Springer

【 摘 要 】

BackgroundZellweger 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.MethodsWe 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.ResultsA 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.ConclusionWe 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】

CC BY   
© Levesque et al.; licensee BioMed Central Ltd. 2012