Principles of genetic variations and molecular diseases: applications in hemophilia A.
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 increasingly innovative technologies, our knowledge of the human genome and genetic diseases has grown considerably over the last few years, allowing us to detect another class of variants affecting 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, ranging in size from kilobases to mega bases; changes in the cell's genome size. If the alteration is located within 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.
Hemostasis and Thrombosis Unit, Hemophilia Clinic, Division of Hematology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium. Electronic address: nlannoy@dmsnet.be.
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Lannoy
Hemostasis and Thrombosis Unit, Hemophilia Clinic, Division of Hematology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
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Hermans
D000818:Animals; D002877:Chromosomes, Human; D004247:DNA / Q000235:genetics; D005169:Factor VIII / Q000235:genetics; D014644:Genetic Variation; D015894:Genome, Human; D006467:Hemophilia A / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans
D005169:Factor VIII; D004247:DNA
CNV; F8 gene mutations; Gene targeting; Hemophilia A; Inversion; Molecular Biology methods; Mutation analysis