Four Decades of Carrier Detection and Prenatal Diagnosis in Hemophilia A: Historical Overview, State of the Art and Future Directions

Rima Dardik; Szymon Janczar; Shadan Lalezari; Einat Avishai; Sarina Levy-Mendelovich; Assaf Arie Barg; Uri Martinowitz; Katarzyna Babol-Pokora; Wojciech Mlynarski; Gili Kenet

doi:10.3390/ijms241411846

Four Decades of Carrier Detection and Prenatal Diagnosis in Hemophilia A: Historical Overview, State of the Art and Future Directions

Int J Mol Sci. 2023 Jul 24;24(14):11846. doi: 10.3390/ijms241411846.

Authors

Rima Dardik^{1

2}, Szymon Janczar³, Shadan Lalezari^{1

2}, Einat Avishai^{1

2}, Sarina Levy-Mendelovich^{1

2}, Assaf Arie Barg^{1

2}, Uri Martinowitz¹, Katarzyna Babol-Pokora³, Wojciech Mlynarski³, Gili Kenet^{1

2}

Affiliations

¹ National Hemophilia Center, Sheba Medical Center, Ramat Gan 52621, Israel.
² Amalia Biron Research Institute of Thrombosis and Hemostasis, Sackler School of Medicine, Tel Aviv University, Tel Aviv 52621, Israel.
³ Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 90-419 Lodz, Poland.

Abstract

Hemophilia A (HA), a rare recessive X-linked bleeding disorder, is caused by either deficiency or dysfunction of coagulation factor VIII (FVIII) resulting from deleterious mutations in the F8 gene encoding FVIII. Over the last 4 decades, the methods aimed at determining the HA carrier status in female relatives of HA patients have evolved from phenotypic studies based on coagulation tests providing merely probabilistic results, via genetic linkage studies based on polymorphic markers providing more accurate results, to next generation sequencing studies enabling highly precise identification of the causative F8 mutation. In parallel, the options for prenatal diagnosis of HA have progressed from examination of FVIII levels in fetal blood samples at weeks 20-22 of pregnancy to genetic analysis of fetal DNA extracted from chorionic villus tissue at weeks 11-14 of pregnancy. In some countries, in vitro fertilization (IVF) combined with preimplantation genetic diagnosis (PGD) has gradually become the procedure of choice for HA carriers who wish to prevent further transmission of HA without the need to undergo termination of pregnancies diagnosed with affected fetuses. In rare cases, genetic analysis of a HA carrier might be complicated by skewed X chromosome inactivation (XCI) of her non-hemophilic X chromosome, thus leading to the phenotypic manifestation of moderate to severe HA. Such skewed XCI may be associated with deleterious mutations in X-linked genes located on the non-hemophilic X chromosome, which should be considered in the process of genetic counseling and PGD planning for the symptomatic HA carrier. Therefore, whole exome sequencing, combined with X-chromosome targeted bioinformatic analysis, is highly recommended for symptomatic HA carriers diagnosed with skewed XCI in order to identify additional deleterious mutations potentially involved in XCI skewing. Identification of such mutations, which may profoundly impact the reproductive choices of HA carriers with skewed XCI, is extremely important.

Keywords: F8 gene; X chromosome inactivation; carrier detection; factor VIII; hemophilia A; preimplantation genetic diagnosis; prenatal diagnosis; whole-exome sequencing.

Publication types

Review

MeSH terms

Factor VIII / genetics
Female
Genetic Carrier Screening
Hemophilia A* / diagnosis
Hemophilia A* / genetics
Heterozygote
Humans
Mutation
Pregnancy
Prenatal Diagnosis / methods

Substances

Factor VIII

Grants and funding

This research received no external funding.