EPOS

European Paediatric Ophthalmological Society

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FOXL2 AND BPES: MUTATIONAL HOTSPOTS, INTRAFAMILIAL VARIABILITY AND REVISION OF THE GENOTYPE- PHENOTYPE CORRELATION

Elfride De Baere (1)+ *, Diane Beysen (1)*, Christine Oley (2), Birgit Lorenz (3), Paul De Sutter (1), Koen Devriendt (4), Michael Dixon (5), Jean-Pierre Fryns (4), Arturo Garza (6), Christoffer Jonsrud (7), Pasi Koivisto (8), Amanda Krause (9), Bart Leroy (1), Françoise Meire (1), Astrid Plomp (10), Lionel Van Maldergem (11), Anne De Paepe (1), Julie Cocquet (12), Marc Fellous (12), Reiner Veitia (12), Ludwine Messiaen (1)
* These authors contributed equally to this work.

(1) Dept. Of Medical Genetics, Gynaecology and Ophthalmology, Ghent University Hospital, Ghent, Belgium; (2) Queensland Clinical Genetics Service, Royal Children's Hospital, Brisbane, Australia; (3) Dept. of Paediatric Ophthalmology, Strabismology and Ophthalmogenetics, Klinikum der Universität Regensburg, Germany; (4) Centre for Human Genetics, Leuven, Belgium; (5) School of Biological Sciences, Stopford Building, University of Manchester, Manchester, UK (6) Grupo Trans-Americano de Esterilidad y Fertilidad, Mexico; (7) University Hospital of Tromsø, Dept. of Medical Genetics, Norway; (8) Dept. of Clinical Genetics, Tampere University Hospital, Finland; (9) Dept. of Human Genetics, National Health Laboratory Service, Johannesburg, South-Africa; (10) AMC, Universiteit van Amsterdam, Klinische Genetica, Nederland; (11) Centre de Génétique Humaine, Loverval, Belgium; (12) Immunogénétique Humaine, Institut Pasteur, Paris, France

+ Address for correspondence:
Elfride De Baere, MD, PhD
Department of Medical Genetics
Ghent University Hospital, De Pintelaan 185, B- 9000 Ghent, Belgium
Phone: 32-9-240.3972. Fax: 32-9-240.4970. Email: Elfride.DeBaere@rug.ac.be

Abstract
The blepharophimosis syndrome (BPES) is an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF). Both types have recently been ascribed to mutations in FOXL2, a putative forkhead transcription factor. We previously reported twenty-two FOXL2 mutations. We and others demonstrated a genotype-phenotype correlation: predicted truncated proteins lead to BPES type I, while predicted extended proteins cause BPES type II. Here, we analyzed FOXL2 in a series of unrelated BPES patients through sequencing of ORF, 5' UTR and putative core promotor, and through FISH analysis. We describe twenty-one new FOXL2 mutations (fifteen novel ones). Our study suggests the existence of two mutational hotspots: 30 % of FOXL2 mutations are in-frame polyalanine expansions and 13 % are a novel out-of-frame duplication. In addition, our study is the first to show that the designation of a BPES family to type I or II is not always possible as we observed intrafamilial variability (both BPES types within the same family due to the same mutation). Furthermore, this study allows a revision of the current genotype-phenotype correlation since we found exceptions against it. We assume that for predicted proteins with a truncation before the polyalanine tract, the risk for development of POF is high. For mutations leading to a predicted truncated or extended protein containing an intact forkhead and polyalanine tract no safe predictions are possible so far. Interestingly, some of these mutations lead to both types of BPES, even within the same family. Polyalanine expansions may lead to BPES type II. For missense mutations no predictions can be done yet. Microdeletions are associated with mental retardation. We conclude that molecular testing may be carefully used as a predictor for POF risk in a limited number of mutations.