Locus BPES FOXL2

Blepharophimosis, Ptosis, and Epicanthus Inversus syndrome (BPES) is an ophthalmic disorder characterized by blepharophimosis, ptosis, epicanthus inversus, and telecanthus, that can appear associated with (type I) or without premature ovarian failure (POF) (type II)¹.

Prevalence

0.3 50,000

1 in 50,000 births globally for all BPES, with FOXL2 expansions ~30% of pathogenic variants^2,3,4. Found worldwide, without differences in prevalence based on sex/ethnicity².

Age of Onset

0 (birth)

HPO Terms

–

Association

Mendelian

Locus

hg19 chr3:138664861-138664904

hg38 chr3:138946019-138946062

t2t chr3:141687011-141687054

Details

14 repeats appears highly constrained in humans: homozygous expansions from 14 polyalanines to 19 leads to disease, which can be limited to isolated palpebral defects⁵. Heterozygous expansions to 24 polyalanines also lead to disease⁵. Locus start can differ between catalogs, which can affect genotyping.

Mechanism

GoF/LoF

Polyalanine expansion leads to haploinsufficiency, likely due to decreased protein availability due to mislocalization following nuclear inclusion^2,5

Detection

Year

2003⁴

Location in Gene

Coding Exon 1

Gene Strand

Alleles

Ref. Motif

NGC

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

NGC

Pathogenic (gene)

CNG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interruption (gene)

–

gnomAD

Pathogenic genotype frequency data is not displayed for this locus because a substantial number of large alleles failed manual review by the gnomAD team.

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0007201

Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome

Hannah,Verdin, Charlotte,Matton, Elfride,De Baere

GeneReviews® · 1993-01-01

genereviews:NBK1441

Resources for Genetics Professionals — Genetic Disorders Caused by Nucleotide Repeat Expansions and Contractions

Stephanie E.,Wallace, Lora JH,Bean

GeneReviews® [Internet] · 2022-10-20

genereviews:NBK535148

FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.

Elfride,De Baere, Diane,Beysen, Christine,Oley, Birgit,Lorenz, Julie,Cocquet, Paul,De Sutter, Koen,Devriendt, Michael,Dixon, Marc,Fellous, Jean-Pierre,Fryns, Arturo,Garza, Christoffer,Jonsrud, Pasi A,Koivisto, Amanda,Krause, Bart P,Leroy, Françoise,Meire, Astrid,Plomp, Lionel,Van Maldergem, Anne,De Paepe, Reiner,Veitia, Ludwine,Messiaen

American journal of human genetics · 2003-01-14

pmid:12529855

A recurrent polyalanine expansion in the transcription factor FOXL2 induces extensive nuclear and cytoplasmic protein aggregation.

S,Caburet, A,Demarez, L,Moumné, M,Fellous, E,De Baere, R A,Veitia

Journal of medical genetics · 2004-12-01

pmid:15591279

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

The combination of polyalanine expansion mutation and a novel missense substitution in transcription factor FOXL2 leads to different ovarian phenotypes in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) patients.

Jiayan,Fan, Yixiong,Zhou, Xiaolin,Huang, Leilei,Zhang, Yuting,Yao, Xin,Song, Junzhao,Chen, Jifan,Hu, Shengfang,Ge, Huaidong,Song, Xianqun,Fan

Human reproduction (Oxford, England) · 2012-08-27

pmid:22926839

Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development.

Lara,Moumné, Aurélie,Dipietromaria, Frank,Batista, Ayhan,Kocer, Marc,Fellous, Eric,Pailhoux, Reiner A,Veitia

Human molecular genetics · 2007-12-24

pmid:18158309

A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction.

Jeyabalan,Nallathambi, Lara,Moumné, Elfride,De Baere, Diane,Beysen, Kim,Usha, Periasamy,Sundaresan, Reiner A,Veitia

Human genetics · 2006-11-07

pmid:17089161

Definition of the blepharophimosis, ptosis, epicanthus inversus syndrome critical region at chromosome 3q23 based on the analysis of chromosomal anomalies.

C T,Lawson, C,Toomes, A,Fryer, M J,Carette, G M,Taylor, Y,Fukushima, M J,Dixon

Human molecular genetics · 1995-05-01

pmid:7633459