Fanconi Anaemia (FA) is a rare disorder with autosomal recessive inheritance, impacting multiple bodily systems. FA involves progressive bone marrow failure, cancer susceptibility, limb defects, reduced fertility in male, and females. The condition is a result of mutations in any of the 23 known FANC genes within the FA pathway, which repairs inter-strand crosslinks, a consequence of spontaneous DNA damage in somatic cells.
FANCM is a crucial gene in the FA pathway which acts as a DNA translocase and has been shown to maintain genomic stability. Loss of FANCM correlates with reduced fertility in humans and mice, likely due to disruptions in normal gametogenesis. A mouse model, bred over five generations, showed a significant decline in fertility among Fancm-/- mice, indicating a heritable component. Genomic instability analysis revealed a significant increase in de novo and inherited structural variants (SVs) in Fancm-/- mice, compared to a control population. Furthermore, breakpoint analysis of SVs showed higher levels of micro-homology mediated end joining (MMEJ), suggesting a possible deficiency in homologous repair (HR). The Fancm-/- mice also exhibited a higher frequency of meiotic crossovers (COs), which appear to be correlated to SV locations, along with increased rates of aneuploidy- each of which may be impacting gamete development or fertilization.
Enhanced understanding of the genetic mechanisms driving reduced fertility in FA is of interest to the FA community. Given the improvements in health outcomes and life expectancy, there is a growing interest in exploring fertility options for individuals with FA. Exploring the role of genomic instability and its impact of gamete development and fertility could deepen our understanding of the FA pathway, and its influence on reproductive biology, with the potential to shed light on broader cases of unexplained fertility beyond FA.