Abstract
AbstractPurpose: Peroxisome biogenesis disorders (PBDs; MIM# 601539) are heterogeneous disorders caused by defects in genes encoding proteins that are essential for peroxisomal matrix and membrane proteins. Heimler syndrome is one of PBDs that is caused by mutations in PEX1 and PEX6 genes. In this study, we aimed to fully characterize the clinical and molecular aspects of two Saudi probands who were diagnosed early as Usher syndrome.Methods: We set up a comprehensive clinical and molecular genetic workflow including detailed ophthalmological, audiological and systemic assessments followed by genome‐wide SNP microarrays analysis and targeted PEX6 gene screening by Sanger sequencing.Results: Clinically: both patients appeared dysmorphic with long faces, high forehead, short nose, small low set ears, and full lips. The ophthalmological assessment revealed advanced inherited retinal dysfunction represented by waxy pallor optic disc, attenuated vessels, RPE mottling with intraretinal bony spicules pigmentations and central foveal atrophic changes in both eyes. Both Indexes exhibited bilateral sensory neural hearing loss and amelogenesis imperfecta. Genetically: an autozygous block was identified on chromosome 6p21.1 encompassing PEX6 gene using SNP microarrays. Novel PEX6 (NM_000287.3) c.290 T > G (p.Val97Gly) was found by Sanger sequencing. The identified variant co‐segregated with the phenotype in both families and found to be “likely pathogenic” according to ACMG guidelines.Conclusions: Our study represents the first report of PEX6 associated Heimler syndrome in the middle east and considered to be the third in the literature so far. It highlights the importance of combining molecular diagnosis with the clinical findings to expand our knowledge of PEX6‐related PBDs phenotype and the allelic spectrum for this gene.
Published Version
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