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

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.

Clinical Diagnosis, Biochemical Findings, Genetics and Incidence of Zellweger Syndrome

“…ZS patients may exhibit neocortical dysplasia (particularly a characteristic perisylvian polymicrogyria), a generalized decrease in white matter volume, delayed myelination, bilateral ventricular dilation, and germinolytic cysts (5,21,22). The cysts have a characteristic appearance and can be useful for confirming suspected ZS, as they are easily detected by transfontanelle sonography and magnetic resonance imaging (22). In our present series, a variety of features consistent with ZS were evident in all patients.…”

“…In the absence of a distinct clinical presentation, cerebral magnetic resonance imaging identifies several rather characteristic features in patients with peroxisomal disorders and is often a valuable tool in terms of diagnostic workup (21,22). ZS patients may exhibit neocortical dysplasia (particularly a characteristic perisylvian polymicrogyria), a generalized decrease in white matter volume, delayed myelination, bilateral ventricular dilation, and germinolytic cysts (5,21,22). The cysts have a characteristic appearance and can be useful for confirming suspected ZS, as they are easily detected by transfontanelle sonography and magnetic resonance imaging (22).…”

Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines

“…Next-generation sequencing panels for PEX genes are being used more frequently as a confirmatory test, and may be required for peroxisome disorders that are difficult to resolve by traditional biochemical methods [16,17,34,36–38]. These DNA tests are available on a clinical basis.…”

Child Neurology: Zellweger syndrome

“…1,3,4 The initial published description of ZS described several members of a single family with multiple congenital anomalies involving the brain, liver, and kidneys; the authors aptly described this as a "cerebrohepatorenal" syndrome. 5 While today more is known about the genetics of ZS, the clinical phenotype remains as initially described and is exemplified by the example case (figure).…”