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

Sebastien Levesque,Wing Yan Yik,Pascale Marquis,Nancy E Braverman,Luigi Bouchard,Ken Dewar,Simon-Pierre Guay,Josee Villeneuve,Sarn Jiralerspong,Charles Morin,Steven Steinberg,Joseph G Hacia

doi:10.1186/1471-2350-13-72

Abstract

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.

Highlights

Zellweger syndrome (ZS) is a peroxisome biogenesis disorder due to mutations in any one of 13 PEX genes
Peroxisome biogenesis disorders (PBD) are classified into two diagnostic groups, Rhizomelic Chondrodysplasia Punctata Type 1 (MIM #215100) and Zellweger spectrum disorder (ZSD), which includes the phenotypes of Zellweger syndrome (ZS) (MIM #214100), neonatal adrenoleukodystrophy (MIM #202370) and infantile Refsum disease (MIM #266510)
We reviewed all values of plasma very long chain fatty acids (VLCFA) performed by gas chromatography–mass spectrometry [19] at the reference center for Quebec (Centre Hospitalier Universitaire de Sherbrooke), starting in 1992

Summary

Introduction

Zellweger syndrome (ZS) is a peroxisome biogenesis disorder due to mutations in any one of 13 PEX genes. Peroxisome biogenesis disorders (PBD; MIM #601539) are autosomal recessive disorders characterized by defective peroxisome assembly, division and/or impaired importation of matrix enzymes [1]. This results in multiple peroxisomal enzymes deficiencies, leading to developmental defects and progressive neurological involvement. ZS is panethnic with an overall incidence estimated to be 1 in 50,000 births in the United States [2] It is genetically heterogeneous and can be caused by mutations in any of 13 PEX genes [1,3]. Hierarchal sequencing of a subset of PEX genes and exons, or complementation studies are used for mutation identification [4,5,7]

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