Variant curation of the largest compendium of FOXL2 coding and non-coding sequence and structural variants in BPES
Matton, C.; Van De Velde, J.; De Bruyne, M.; Van De Sompele, S.; Hooghe, S.; Syryn, H.; Bauwens, M.; D'haene, E.; Dheedene, A.; Cools, M.; Komatsuzaki, S.; Preizner-Rzucidlo, E.; Ross, A.; Armstrong, C.; Watkins, W.; Shelling, A.; Vincent, A. L.; Cassiman, C.; Vermeer, S.; Bunyan, D. J.; Verdin, H.; De Baere, E.
Show abstract
Heterozygous FOXL2 (non-)coding sequence and structural variants (SVs) lead to blepharophimosis, ptosis and epicanthus inversus syndrome (BPES), a rare, autosomal dominant developmental disorder characterized by a completely penetrant eyelid malformation and incompletely penetrant primary ovarian insufficiency (POI). We collected variants from our in-house database, generated via clinical genetic testing and downstream research testing in the Center for Medical Genetics Ghent, Belgium (2001-2024), and via literature and other resources in the same period. All retrieved variants were categorized using ACMG/AMP classifications to increase the knowledge of pathogenicity. We collected 413 unique genetic defects of the FOXL2 region, including 76 novel variants, in 864 index patients. Of these, 87% of patients were identified with a coding FOXL2 sequence variant. The polyalanine tract is a known mutational hotspot of FOXL2, illustrated here by the high percentage of pathogenic polyalanine expansions (24%). Furthermore, the molecular spectrum in typical BPES index patients is characterized by 8% coding deletions and 3% deletions located up- and downstream of FOXL2. The remaining 2% carry translocations along with chromosomal rearrangements of 3q23. This uniform and structured reclassification, incorporating the largest dataset of variants implicated in FOXL2-associated disease so far, will improve both the diagnosis as well as genetic counselling for individuals with BPES.
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