Clinical and genetic studies of 17 Han Chinese pedigrees and 31 sporadic patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

Purpose: To investigate the molecular pathogenesis of a large group of Han Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), and to evaluate the correlation between the phenotype and genotype for these patients.

Methods: Seventy-six affected individuals, including 45 patients from 17 pedigrees and 31 sporadic patients, were recruited with their family members. All participants underwent complete clinical examinations and were classified as having type I or II based on whether they had premature ovarian failure. The patients' genomic DNA was extracted. A genetic test was performed with direct sequencing of the coding regions of the forkhead transcriptional factor 2 ( FOXL2 ) gene. Variations were analyzed using online databases and programs. Genotype-phenotype correction was investigated.

Results: Seventy-six affected and 75 unaffected individuals underwent clinical evaluations and genetic testing. Only one family was diagnosed with type I; the others could not be classified because of a lack of female patients or a definite history of premature ovarian failure. Twenty-seven variations were identified, including 12 novel and 15 previously reported variations. Six variations were detected repeatedly in different nonconsanguineous pedigrees. Four indel variations, located in the alanine/proline-rich region of the FOXL2 gene, presented with a relatively higher frequency. Two rare double variations were detected in two sporadic patients. FOXL2 gene variations were not detected in five sporadic patients. The phenotype varied among different families and patients, although they carried the same variations.

Conclusions: We identified 12 novel variations in the FOXL2 gene that would expand the spectrum of the FOXL2 variation database. In addition, we found that the alanine/proline-rich region is a variation hotspot in the FOXL2 gene. The genotype-phenotype correlation is not easy to establish due to clinical and genetic heterogeneity.