BPES_FOXL2
- Gene
- FOXL2
- Disease
- BPES
- Inheritance
- AD/AR
- Classification
- Definitive
- Total Score
- 14.5
- Publications Reviewed
- 6
- Publication Span
- 19.47 years
- Last Updated
- 06/04/2025
- Curator(s)
- Laurel Hiatt
Description
FOXL2 pathogenic variants, including polyalanine-tract expansions, are associated with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), an eyelid malformation syndrome with or without premature ovarian failure. Reported evidence includes multiple unrelated probands and families with heterozygous FOXL2 variants, segregation of a polyalanine expansion in a multigeneration BPES type II family, absence from controls/population databases, conservation and in silico support for a polyalanine-region insertion, and experimental data showing altered FOXL2 localization, aggregation, transactivation, and BPES-like eyelid/ovarian phenotypes in models.
Genetic evidence
Total: 9
| Singular Evidence | Probands | PMID:11468277 | 2.5 | FOXL2 screening in BPES type I/II/unknown and sporadic cases identified 21 coding mutations and one microdeletion in 67% of BPES patients; variants included familial and sporadic BPES and were absent from 200 control chromosomes and tested unaffected relatives. Evidence is gene-level and includes both polyalanine-expansion and non-repeat FOXL2 variants. |
| Singular Evidence | Probands | PMID:27283035 | 3.5 | Among 14 Czech/Slovak BPES probands, 13 (93%) carried pathogenic heterozygous FOXL2 variants, including three novel variants, six polyalanine-expansion duplications, two frameshift duplications, one frameshift deletion, and one FOXL2 ORF deletion; all probands had typical ocular BPES. Evidence is gene-level and includes repeat and non-repeat FOXL2 variants. |
| Collective Evidence | Computational | PMID:33875939 | 1 | The FOXL2 polyalanine insertion c.672_701insGCGGCTGCCGCCGCAGCTGCTGCAGGCGCT (p.Ala234_Gly235linsAAAAAAAAGA) expands the polyalanine tract from 14 to 24 residues, was absent from population databases, affected a conserved region, and was predicted damaging/disease-causing by MutationTaster (score 1), PolyPhen-2 (score 1.000), and SIFT (score 0.00). |
| Collective Evidence | Segregation | PMID:33875939 | 2 | In a four-generation Chinese BPES type II family, the FOXL2 polyalanine insertion p.Ala234_Gly235linsAAAAAAAAGA was present in all 13 tested affected individuals and absent from 8 unaffected relatives by sequencing; no LOD score was reported. |
Experimental evidence
Total: 5.5
| Models | Cell culture | PMID:15591279 | 1 | COS-7 cells expressing the FOXL2-Ala24 polyalanine-expansion construct showed intranuclear aggregates and marked cytoplasmic mislocalization/aggregation compared with predominantly nuclear wild-type FOXL2-Ala14; immunofluorescence confirmed the findings, and co-transfection suggested mutant and wild-type FOXL2 can co-aggregate. |
| Functional Alteration | Non-patient cells | PMID:18372316 | 0.5 | COS-7 localization assays and KGN granulosa-like luciferase assays of 17 disease-causing FOXL2 missense mutants showed that many forkhead-domain mutants cause nuclear/cytoplasmic mislocalization and aggregation with impaired transactivation. Evidence is gene-level and not specific to the polyalanine repeat locus. |
| Models | Non-human model organism | PMID:22248822 | 4 | Review summarizes two Foxl2 knockout mouse models and the Polled Intersex Syndrome goat regulatory-deletion model: surviving homozygous mice show BPES-like severe eyelid malformation/open eyes at birth and ovarian failure, while goat and conditional mouse data support FOXL2 roles in ovarian development/maintenance. Evidence is gene-level and not tandem-repeat-specific. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.