EPOS

European Paediatric Ophthalmological Society

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Disruptions of distant regulatory elements surrounding FOXL2 in the causation of BPES syndrome

De Baere Elfride¹, D'haene Barbara¹, Attanasio Catia², Lemire Edmond³, Lorenz Birgit⁴, Antonarakis Stylianos²
¹Center for Medical Genetics, Ghent University Hospital, Belgium, ²Department of Genetic Medicine and Development, University of Geneva Medical School, Switzerland, ³Division of Medical Genetics, Royal University Hospital, Saskatoon, Canada, ⁴Department of Ophthalmology, Universitaetsklinikum Giessen and Marburg Giessen Campus, Germany

Introduction: Blepharophimosis syndrome (BPES) is a development disorder caused by FOXL2 mutations, total gene deletions or long-range microdeletions. In 12% of patients however, the molecular defect remains unknown. The major aim of this study was to explore the role of subtle copy number changes and variations in conserved non-coding sequences (CNCs) in order to unravel the underlying genetic defect in a panel of 40 patients without intragenic FOXL2 mutations/deletions. Methods: We developed a combined strategy, consisting of arrayCGH, quantitative PCR (qPCR) and sequencing of CNCs located in the shortest region of overlap (SRO) of previously described microdeletions upstream of FOXL2. Results: ArrayCGH and qPCR of the FOXL2 region revealed 5 new microdeletions 5' to FOXL2. Interestingly, one of this is a very subtle deletion containing an important regulatory element. Overall, the breakpoints of these new microdeletions are scattered. The phenotypes of the five BPES patients carrying these deletions were indistinguishable from those of patients carrying an intragenic mutation. Sequencing of CNCs in the SRO showed that sequence variations in CNCs do not play a major role in the molecular pathogenesis of BPES. Conclusion: Our study emphasizes the importance of disruptions of distant regulatory elements surrounding FOXL2 in the causation of BPES, and the need for a highly sensitive copy number screening of the FOXL2 region in this development disorder.