Blepharophimosis-Ptosis-Epicanthus Inversus syndrome (BPES) via the FOXL2 Gene

Summary and Pricing

Test Method

Bi-Directional Sanger Sequencing
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
1673 FOXL2 81479 81479 $610 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
1673FOXL281479 $610 Order Options and Pricing

Pricing Comments

CNV detection may be ordered through Test #600.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

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For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

12 days on average

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Geneticist

Clinical Features and Genetics

Clinical Features

Blepharophimosis-Ptosis-Epicanthus Inversus syndrome (BPES) is a dominantly inherited developmental disorder of the eyelids, which may severely impair visual function (Amati et al. 1995). BPES is clinically characterized by four major ophthalmic manifestations that are present at birth: blepharophimosis (shortening of the horizontal palpebral fissure), ptosis (droopy eyelids), epicanthus inversus (a vertical fold of the skin that stretches from the lower eyelid near the inner corner of the eye and towards either side of the nose), and telecanthus (lateral displacement of the inner canthi that leads to abnormal interpupillary distance) (Zahanova et al. 2012). Clinically, two types of BPES have been recognized. BPES Type I includes female infertility as a result of premature ovarian failure (POF) along with the four major ophthalmic manifestations described above. BPES Type II is limited to the four major eyelid abnormalities (Zahanova et al. 2012; Alao et al. 2012). Patients with BPES have a high incidence of bilateral strabismus, amblyopia and refractive errors (Choi et al. 2006). Ptosis with strabismus doubles the risk of amblyopia. Patients who have severe ptosis are recommended to have surgery before 3 years of age, and all other patients should undergo surgical repair before 5 years of age (Beckingsale et al. 2003). Also, premature ovarian failure can be corrected with hormone replacement therapy. Other symptoms of BPES include lacrimal duct anomalies, a broad nasal bridge, low-set ears, and a short philtrum (abnormal distance between the upper lip and the nose) (De Baere 2009).

Genetics

Blepharophimosis-Ptosis-Epicanthus Inversus syndrome is a dominantly inherited developmental disorder. Mutations in the FOXL2 gene, which is located on chromosome 3q23, has been shown to be causative for both BPES Type I and II. FOXL2 belongs to the winged helix /forkhead (FH) transcription factor gene family, which is known to be involved in a diverse range of developmental processes such as establishment of the body axis and the development of tissues from all three germ layers (Lehmann et al. 2003). FOXL2 is a single-exon gene encoding a highly conserved protein that contains a 110-amino-acid DNA-binding forkhead domain and a poly alanine tract of 14 residues that is conserved in mammals. FOXL2 is been reported to be expressed in the mesenchyme of the developing eyelids and in fetal and adult ovarian follicles (Crisponi et al. 2001; Beysen et al. 2009). Currently, four of the 11 human FH genes that are shown to be causative for human hereditary developmental disorders exhibit an ocular phenotype (Verdin and De Baere 2012).

Of all genetic defects found, approximately 71% are intragenic mutations of FOXL2, 10–12% are deletions encompassing FOXL2, and 5% are deletions located outside its transcription unit (Beysen et al., 2009; D’haene et al. 2009; D’haene et al. 2010). Genotype-phenotype correlations indicated that the patients with mutations that result in proteins with truncation before the poly-Ala tract are at high risk for developing POF (BPES type I). Expansion of poly-Ala tract may lead to BPES type II. However, several exceptions to this correlation were found (De Baere et al. 2003). The largest group in the intragenic mutations is frameshift mutations (44%) followed by in-frame changes (33%), nonsense mutations (12%) and finally missense mutations (11%). The majority of the in-frame mutations (93%) lead to polyalanine expansions, representing the most important mutational hotspot in FOXL2 (Verdin and De Baere 2012; De Baere et al. 2003). BPES Patients with large interstitial deletions encompassing FOXL2 may present other clinical findings, such as microcephaly, mild mental retardation and growth delay (D’haene et al., 2009; de Ru et al. 2005). So far, about 200 FOXL2 pathogenic sequence variations (missense, nonsense, small and gross insertions/duplications and Complex rearrangements) have been reported in BPES (Human Gene Mutation Database). Mutations in the core promoter region as well as the 3'-UTR of FOXL2 have been reported in BPES patients (Li et al. 2009; Chawla et al. 2013)

Testing Strategy

This test involves bidirectional Sanger sequencing of all coding exons and splice sites of the FOXL2 gene. The full coding sequence of each exon plus ~10 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) in family members of patients with a known pathogenic variant or to confirm research results.

This test also covers the three noncoding FOXL2 variants (c.*86C>T; c.*619C>A; c.-251G>A) that have been reported to be causative for BPES (Human Gene Mutation Database).

Clinical Sensitivity - Sanger Sequencing

A FOXL2 mutation analysis in two different studies identified mutations in 65-72% of the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) patients (De Baere et al. 2001; Beysen et al. 2008; De Baere 2009)

Indications for Test

All patients with symptoms suggestive of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II.

Gene

Official Gene Symbol OMIM ID
FOXL2 605597
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Blepharophimosis, Ptosis, And Epicanthus Inversus AD 110100

Related Test

Name
Premature Ovarian Failure (POF) Panel

Citations

  • Alao MJ, Lalèyè A, Lalya F, Hans C, Abramovicz M, Morice-Picard F, Arveiler B, Lacombe D, Rooryck C. 2012. Blepharophimosis, ptosis, epicanthus inversus syndrome with translocation and deletion at chromosome 3q23 in a black African female. Eur J Med Genet 55: 630–634. PubMed ID: 22906557
  • Amati P, Chomel JC, Nivelon-Chevalier A, Gilgenkrantz S, Kitzis A, Kaplan J, Bonneau D. 1995. A gene for blepharophimosis-ptosis-epicanthus inversus syndrome maps to chromosome 3q23. Hum. Genet. 96: 213–215. PubMed ID: 7635472
  • Beckingsale PS, Sullivan TJ, Wong VA, Oley C. 2003. Blepharophimosis: a recommendation for early surgery in patients with severe ptosis. Clin. Experiment. Ophthalmol. 31: 138–142. PubMed ID: 12648048
  • Beysen D, Jaegere S De, Amor D, Bouchard P, Christin-Maitre S, Fellous M, Touraine P, Grix AW, Hennekam R, Meire F, Oyen N, Wilson LC, et al. 2008. Identification of 34 novel and 56 known FOXL2 mutations in patients with Blepharophimosis syndrome. Hum. Mutat. 29: E205–219. PubMed ID: 18642388
  • Beysen D, Paepe A De, Baere E De. 2009. FOXL2 mutations and genomic rearrangements in BPES. Hum. Mutat. 30: 158–169. PubMed ID: 18726931
  • Chawla B, Bhadange Y, Dada R, Kumar M, Sharma S, Bajaj MS, Pushker N, Chandra M, Ghose S. 2013. Clinical, Radiologic, and Genetic Features in Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome in the Indian Population. Investigative ophthalmology & visual science 54: 2985–2991. PubMed ID: 23513057
  • Choi K-H, Kyung S, Oh SY. 2006. The factors influencing visual development in blepharophimosis-ptosis-epicanthus inversus syndrome. J Pediatr Ophthalmol Strabismus 43: 285–288. PubMed ID: 17022162
  • Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, Bisceglia L, Zelante L, Nagaraja R, Porcu S, Ristaldi MS, Marzella R, et al. 2001. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat. Genet. 27: 159–166. PubMed ID: 11175783
  • de Baere E, Beysen D, Oley C, Lorenz B, Cocquet J, Sutter P De, Devriendt K, Dixon M, Fellous M, Fryns J-P, Garza A, Jonsrud C, et al. 2003. FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. Am. J. Hum. Genet. 72: 478–487. PubMed ID: 12529855
  • de Baere E, Dixon MJ, Small KW, Jabs EW, Leroy BP, Devriendt K, Gillerot Y, Mortier G, Meire F, Maldergem L Van, Courtens W, Hjalgrim H, et al. 2001. Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation. Hum. Mol. Genet. 10: 1591–1600. PubMed ID: 11468277
  • de Baere E. 2009. Blepharophimosis, Ptosis, and Epicanthus Inversus. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301614
  • de Ru MH, Gille JJP, Nieuwint AWM, Bijlsma JB, Blij JF van der, Hagen JM van. 2005. Interstitial deletion in 3q in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and microcephaly, mild mental retardation and growth delay: clinical report and review of the literature. Am. J. Med. Genet. A 137: 81–87. PubMed ID: 16015581
  • D’haene B, Attanasio C, Beysen D, Dostie J, Lemire E, Bouchard P, Field M, Jones K, Lorenz B, Menten B, Buysse K, Pattyn F, et al. 2009. Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening. PLoS Genet. 5: e1000522. PubMed ID: 19543368
  • D’haene B, Nevado J, Pugeat M, Pierquin G, Lowry RB, Reardon W, Delicado A, García-Miñaur S, Palomares M, Courtens W, Stefanova M, Wallace S, et al. 2010. FOXL2 copy number changes in the molecular pathogenesis of BPES: unique cohort of 17 deletions. Hum. Mutat. 31: E1332–1347. PubMed ID: 20232352
  • Human Gene Mutation Database (Bio-base).
  • Lehmann OJ, Sowden JC, Carlsson P, Jordan T, Bhattacharya SS. 2003. Fox’s in development and disease. Trends Genet. 19: 339–344. PubMed ID: 12801727
  • Li D, Zeng W, Tao J, Li S, Liang C, Chen X, Mu W, Wang X, Qin Y, Jie Y, Wei W. 2009. Mutations of the transcription factor FOXL2 gene in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome. Genet Test Mol Biomarkers 13: 257–268. PubMed ID: 19371227
  • Verdin H, Baere E De. 2012. FOXL2 impairment in human disease. Horm Res Paediatr 77: 2–11. PubMed ID: 22248822
  • Zahanova S, Meaney B, Łabieniec B, Verdin H, Baere E De, Nowaczyk MJM. 2012. Blepharophimosis-ptosis-epicanthus inversus syndrome plus: deletion 3q22.3q23 in a patient with characteristic facial features and with genital anomalies, spastic diplegia, and speech delay. Clin. Dysmorphol. 21: 48–52. PubMed ID: 21934608

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