DNA structure alterations are the ultimate source of genetic variations. Without them, evolution would be impossible. While they are essential for DNA diversity, defects
in DNA synthesis can lead to numerous genetic diseases. Due to
increas
ingly
innovative technologies, our knowledge of the human genome and genetic diseases has grown considerably over the last few years, allow
ing us to detect another class of variants affect
ing the chromosomal
structure. DNA sequence can be altered
in multiple ways: DNA sequence changes by substitution, deletion, or duplication of some nucleotides; chromosomal
structure alterations by deletion, duplication, translocation, and
inversion, rang
ing
in size from kilobases to mega bases; changes
in the cell's genome size. If the
alteration is located with
in a gene and sufficiently deleterious, it can cause genetic disorders.
Due to the F8 gene’s high rate of new small mutations and its location at the tip of X chromosome, containing high repetitive sequences, a wide variety of genetic variants has been described as the cause of hemophilia A (HA). In addition to the F8 intron 22 repeat inversion, HA can also result from point mutations, other inversions, complex rearrangements, such as duplications or deletions, and transposon insertions causing phenotypes of variable severity characterized by complete or partial deficiency of circulating FVIII.
This review aims to present the origins, mechanisms, and consequences of F8 alterations. A sound understanding of the multiple genetic mechanisms responsible for HA is essential to determine the appropriate strategy for molecular diagnosis and detected each type of genetic variant.