Canine XX Disorders/Differences of Sex Development (SRY-Negative): A Potential Role for the FOXL2 Gene

Disorders/differences of sex development (DSDs) comprise a group of congenital conditions characterized by atypical gonadal and/or anatomical development of the reproductive system. Among them, XX DSD (SRY-negative) represents a rare but clinically relevant condition, defined by the presence of testicular or ovotesticular tissue in chromosomal females lacking the SRY gene. This phenotype has been described in humans and several domestic species, including dogs, cats, and goats.

Over the past decades, studies in dogs with 78,XX DSD (SRY-negative) have primarily focused on identifying causative mutations in candidate genes, particularly in SOX9. However, only a limited number of cases have been associated with SOX9 copy number variations, suggesting that additional genetic factors remain to be identified. In contrast, FOXL2, a key regulator of ovarian development and maintenance, has been relatively underexplored in canine studies. Functional evidence from mouse models highlights the importance of FOXL2 in ovarian differentiation and maintenance, as well as in craniofacial and skeletal development. 78,XX DSD has been increasingly reported in French Bulldogs, a breed predisposed to craniofacial and ocular abnormalities.

Current evidence indicates that FOXL2 is a biologically plausible candidate gene for 78,XX DSD in dogs, although no causative variants have yet been identified. The observed cryptic relatedness among affected French Bulldogs suggests a shared genetic background. Future studies should include comprehensive sequencing of FOXL2, particularly its GC-rich coding regions, together with detailed clinical phenotyping. Integrating molecular and clinical data may improve understanding of the genetic basis of XX DSD and support more informed breeding strategies.