Genetic and Clinical Features of FOXL2 ‐Associated Blepharophimosis–Ptosis–Epicanthus Inversus Syndrome Based on 11 Chinese Families and Literature Review

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), caused by FOXL2 variants, has been divided into two subtypes by eyelid abnormalities with (BPES-I) or without (BPES-II) primary ovarian insufficiency (POI). This study investigated the genetic and phenotypic characteristics of FOXL2-associated BPES and their genotype-phenotype correlations. FOXL2 variants were identified by in-house next-generation sequencing and compared with public databases. Clinical features were also summarized. Eleven FOXL2 variants, including four novel, were detected in 11 families from our cohort. Based on literature, 273 FOXL2 pathogenic/likely pathogenic variants were reviewed in 650 patients from 548 families. Nearly half (47.6%, 130/273) of the variants were truncation. The most frequent (24.0%, 132/549) variant was p.A225_A234dup. In the polyalanine tract, variants leading to the deletion of 1-10 or expansion/insertion of 2 alanine residues were likely benign, whereas variants causing the expansion/insertion of 10-15 alanine residues were pathogenic. The proportion of truncation variants was significantly higher in patients with BPES-I (73.8%, 48/65) than in those with BPES-II (19.6%, 19/97). In conclusion, the pathogenicity of in-frame variants within the polyalanine tract was associated with the number of polyalanine residues. Truncation variants were frequently linked to the severe phenotype (BPES-I), highlighting their potential value in clinical diagnosis and patient management, particularly for preventing or treating POI.