Shifting the landscape: Dominant C‐terminal rare missense FOXL2 variants in non‐syndromic primary ovarian failure etiology

• Published in: Clinical genetics Vol. 106; no. 1; pp. 102 - 108
• Main Authors: Jordan, Pénélope, Verebi, Camille, Hervé, Bérénice, Perol, Sandrine, Chakhtoura, Zeina, Courtillot, Carine, Bachelot, Anne, Karila, Daphné, Renard, Céline, Grouthier, Virginie, Croix, Stanislas Mulot, Bernard, Valérie, Fouveaut, Corinne, Perrière, Aude Brac, Jonard‐Catteau, Sophie, Touraine, Philippe, Plu‐Bureau, Geneviève, Dupont, Jean Michel, Christin‐Maitre, Sophie, Bienvenu, Thierry
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-07-2024; Wiley
• Series: Clinical Genetics
• Subjects: Blepharophimosis; FOXL2; FOXL2 gene; Genetic screening; Life Sciences; missense variants; Ovaries; premature ovarian insufficiency; Reproductive status; Risk factors; premature ovarian insufficiency; FOXL2; missense variants
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.14526

Pathogenic germline variants in the FOXL2 gene are associated with Blepharophimosis, Ptosis, and Epicanthus Inversus syndrome (BPES) in humans, an autosomal dominant condition. Two forms of BPES have emerged: (i) type I (BPES‐I), characterized by ocular signs and primary ovarian failure (POI), and (ii) type II (BPES‐II) with no systemic associations. This study aimed to compare the distribution of FOXL2 variants in idiopathic POI/DOR (diminished ovarian reserve) and both types of BPES, and to determine the involvement of FOXL2 in non‐syndromic forms of POI/DOR. We studied the whole coding region of the FOXL2 gene using next‐generation sequencing in 1282 patients with non‐syndromic POI/DOR. Each identified FOXL2 variant was compared to its frequency in the general population, considering ethnicity. Screening of the entire coding region of the FOXL2 gene allowed us to identify 10 different variants, including nine missense variants. Of the patients with POI/DOR, 14 (1%) carried a FOXL2 variant. Significantly, six out of nine missense variants (67%) were overrepresented in our POI/DOR cohort compared to the general or specific ethnic subgroups. Our findings strongly suggest that five rare missense variants, mainly located in the C‐terminal region of FOXL2 are high‐risk factors for non‐syndromic POI/DOR, though FOXL2 gene implication accounts for approximately 0.54% of non‐syndromic POI/DOR cases. These results support the implementation of routine genetic screening for patients with POI/DOR in clinical settings.
Putative phenotypic impact of FOXL2 variants. The different sub‐units of the preproprotein are indicated: the peptide signal (gray); the poly‐glycine region (green); the Forkhead region (yellow); the two conserved poly‐alanine regions (red) and the poly‐proline region (dark blue). The three phenotypes are indicated: Blepharophimosis, ptosis, and epicanthus inversus syndrome with primary ovarian failure type I (BPES‐I), Blepharophimosis, ptosis, and epicanthus inversus syndrome with no primary ovarian failure type II (BPES‐II), and Primary ovarian failure (POI). Black asterisks indicated the location of the most frequent point pathogenic variants.