Curation BPES FOXL2

Gene FOXL2

Disease BPES

Inheritance AD/AR

Score

9 + 5.5 = 14.5 / 18

Genetic + experimental = total

Classification

Definitive

Refuted

Moderate

Definitive

Last Updated 06/04/2025

Pubs Reviewed 6

Publication Span 19.47 years

Publication Interval 19.47 years

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.

All criTRia Curations Locus Page

Genetic evidence

Total: 9

Per page

Category	Type	Citation	Score	Details
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

Per page

Category	Type	Citation	Score	Details
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.

Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.