Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype-phenotype correlation

Mutations in FOXL2, a forkhead transcription factor gene, have recently bee n shown to cause blepharo-phimosis-ptosis-epicanthus inversus syndrome (BPE S) types I and II, a rare genetic disorder. In BPES type I a complex eyelid malformation is associated with premature ovarian failure (POF), whereas i n BPES type II the eyelid defect occurs as an isolated entity. In this stud y, we describe the identification of novel mutations in the FOXL2 gene in B PES types I and II families, in sporadic BPES patients, and in BPES familie s where the type could not be established. In 67% of the patients studied, we identified a mutation in the FOXL2 gene. In total, 21 mutations (17 of w hich are novel) and one microdeletion were identified. Thirteen of these FO XL2 mutations are unique. In this study, we demonstrate that there is a gen otype-phenotype correlation for either types of BPES by the finding that mu tations predicted to result in a truncated protein either lacking or contai ning the forkhead domain lead to BPES type I. In contrast, duplications wit hin or downstream of the forkhead domain, and a frameshift downstream of th em, all predicted to result in an extended protein, cause BPES type II. In addition, in 30 unrelated patients with isolated POF no causal mutations we re identified in FOXL2. Our study provides further evidence that FOXL2 hapl oinsufficiency may cause BPES types I and III by the effect of a null allel e and a hypomorphic allele, respectively. Furthermore, we propose that in a fraction of the BPES patients the genetic defect does not reside within th e coding region of the FOXL2 gene and may be caused by a position effect.