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FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation

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Abstract
Blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF), has recently been ascribed to mutations in FOXL2, a putative forkhead transcription factor gene. We previously reported 22 FOXL2 mutations and suggested a preliminary genotype-phenotype correlation. Here, we describe 21 new FOXL2 mutations (16 novel ones) through sequencing of open reading frame, 5' untranslated region, putative core promoter, and fluorescence in situ hybridization analysis. Our study shows the existence of two mutational hotspots: 30% of FOXL2 mutations lead to polyalanine (poly-Ala) expansions, and 13% are a novel out-of-frame duplication. In addition, this is the first study to demonstrate intra- and interfamilial phenotypic variability (both BPES types caused by the same mutation). Furthermore, the present study allows a revision of the current genotype-phenotype correlation, since we found exceptions to it. We assume that for predicted proteins with a truncation before the poly-Ala tract, the risk for development of POF is high. For mutations leading to a truncated or extended protein containing an intact forkhead and poly-Ala tract, no predictions are possible, since some of these mutations lead to both types of BPES, even within the same family. Poly-Ala expansions may lead to BPES type II. For missense mutations, no correlations can be made 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.
Keywords
EPICANTHUS INVERSUS SYNDROME, PATIENT, GENE, T(3-4)(Q23-P15.2), TRANSLOCATION, BLEPHAROPHIMOSIS, PTOSIS, 3Q23

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Chicago
De Baere, Elfride, DIANE BEYSEN, Christine Oley, Birgit Lorenz, Julie Cocquet, Petra De Sutter, Koen Devriendt, et al. 2003. “FOXL2 and BPES: Mutational Hotspots, Phenotypic Variability, and Revision of the Genotype-phenotype Correlation.” American Journal of Human Genetics 72 (2): 478–487.
APA
De Baere, E., BEYSEN, D., Oley, C., Lorenz, B., Cocquet, J., De Sutter, P., Devriendt, K., et al. (2003). FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. AMERICAN JOURNAL OF HUMAN GENETICS, 72(2), 478–487.
Vancouver
1.
De Baere E, BEYSEN D, Oley C, Lorenz B, Cocquet J, De Sutter P, et al. FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. AMERICAN JOURNAL OF HUMAN GENETICS. 2003;72(2):478–87.
MLA
De Baere, Elfride, DIANE BEYSEN, Christine Oley, et al. “FOXL2 and BPES: Mutational Hotspots, Phenotypic Variability, and Revision of the Genotype-phenotype Correlation.” AMERICAN JOURNAL OF HUMAN GENETICS 72.2 (2003): 478–487. Print.
@article{219647,
  abstract     = {Blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF), has recently been ascribed to mutations in FOXL2, a putative forkhead transcription factor gene. We previously reported 22 FOXL2 mutations and suggested a preliminary genotype-phenotype correlation. Here, we describe 21 new FOXL2 mutations (16 novel ones) through sequencing of open reading frame, 5' untranslated region, putative core promoter, and fluorescence in situ hybridization analysis. Our study shows the existence of two mutational hotspots: 30\% of FOXL2 mutations lead to polyalanine (poly-Ala) expansions, and 13\% are a novel out-of-frame duplication. In addition, this is the first study to demonstrate intra- and interfamilial phenotypic variability (both BPES types caused by the same mutation). Furthermore, the present study allows a revision of the current genotype-phenotype correlation, since we found exceptions to it. We assume that for predicted proteins with a truncation before the poly-Ala tract, the risk for development of POF is high. For mutations leading to a truncated or extended protein containing an intact forkhead and poly-Ala tract, no predictions are possible, since some of these mutations lead to both types of BPES, even within the same family. Poly-Ala expansions may lead to BPES type II. For missense mutations, no correlations can be made 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.},
  author       = {De Baere, Elfride and BEYSEN, DIANE and Oley, Christine and Lorenz, Birgit and Cocquet, Julie and De Sutter, Petra and Devriendt, Koen and Dixon, Michael and Fellous, Marc and Fryns, Jean-Pierre and Garza, Arturo and Jonsrud, Christoffer and Koivisto, Pasi A and Krause, Amanda and Leroy, Bart and Meire, Fran\c{c}oise and Plomp, Astrid and Van Maldergem, Lionel and De Paepe, Anne and Veitia, Reiner and Messiaen, Ludwine},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {EPICANTHUS INVERSUS SYNDROME,PATIENT,GENE,T(3-4)(Q23-P15.2),TRANSLOCATION,BLEPHAROPHIMOSIS,PTOSIS,3Q23},
  language     = {eng},
  number       = {2},
  pages        = {478--487},
  title        = {FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation},
  url          = {http://dx.doi.org/10.1086/346118},
  volume       = {72},
  year         = {2003},
}

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