Structural chromosomal rearrangements result from different mechanisms of formation, usually related to certain genomic architectural features that may lead to genetic instability. Most of these rearrangements arise from recombination, repair, or replication mechanisms that occur after a double-strand break or the stalling/breakage of a replication fork. Here, we review the mechanisms of formation of structural rearrangements, highlighting their main features and differences. The most important mechanisms of constitutional chromosomal alterations are discussed, including Non-Allelic Homologous Recombination (NAHR), Non-Homologous End-Joining (NHEJ), Fork Stalling and Template Switching (FoSTeS), and Microhomology-Mediated Break-Induced Replication (MMBIR). Their involvement in chromoanagenesis and in the formation of complex chromosomal rearrangements, inverted duplications associated with terminal deletions, and ring chromosomes is also outlined. We reinforce the importance of high-resolution analysis to determine the DNA sequence at, and near, their breakpoints in order to infer the mechanisms of formation of structural rearrangements and to reveal how cells respond to DNA damage and repair broken ends.

The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients.

Premature ovarian insufficiency (POI) is the cessation of menstruation before the age of 40 and can result from different etiologies, including genetic, autoimmune, and iatrogenic. Of the genetic causes, single-gene mutations and cytogenetic alterations, such as X-chromosome aneuploidies and chromosome rearrangements, can be associated with POI. In this review, we summarize the genetic factors linked to POI and list the main candidate genes. We discuss the association of these genes with the ovarian development, the functional consequences of different mutational mechanisms and biological processes that are frequently disrupted during POI pathogenesis. Additionally, we focus on the high prevalence of X-autosome translocations involving the critical regions in Xq, known as POI1 and POI2, and discuss in depth the main hypotheses proposed to explain this association. Although the incorrect pairing of chromosomes during meiosis could lead to oocyte apoptosis, the reason for the prevalence of X-chromosome breakpoints at specific regions remains unclear. In most cases, studies on genes disrupted by balanced structural rearrangements cannot explain the ovarian failure. Thus, the position effect has emerged as a putative explanation for genetic mechanisms as translocations possibly result in changes in overall chromatin topology due to chromosome repositioning. Given the tremendous impact of POI on women’s quality of life, we highlight the value of investigations in to the interplay between ovarian function and gene regulation to deepen our understanding of the molecular mechanisms related to this disease, with the ultimate goal of improving patients’ care and assistance.