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

[zellweger syndrome]

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 _815 del , p .[Val 207 _Gln 294 del , Val 76 _Gln 294 del ]) in PEX 6 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 SF 2 /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 PEX 6 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 .