Role and Relevance of Factor VIII Gene Haplotyping for the Indirect Genetic Analysis of Carrier Diagnosis in Hemophilia

Introduction

Hemophilia A is an X-linked recessive inherited bleeding disorder that impairs the body's ability to control blood coagulation because of the deficiency of factor VIII (FVIII). It affects 1 in 5000 to 10,000 male births worldwide [1]. The disease results in greatly delayed clotting time so that a cut that might be completely innocuous to a normal person could bleed for days in a hemophiliac. FVIII or antihemophiliac factor is a trace plasma glycoprotein that plays a central role in normal blood coagulation. The gene for FVIII is large and located near the terminus of the long arm of the X chromosome at Xq28 and is 186 kb long, contains 26 exons () that code for 9 kb mRNA, which translates to the FVIII protein comprising 2351 amino acids. Any defect in FVIII gene leads to hemophilia A.

Abstract

Hemophilia A is an X-linked recessive coagulation disorder because of the quantitative or qualitative deficiency of blood coagulation factor VIII (FVIII). Molecular genetic analysis; that is, direct mutation detection and linkage analysis of restriction markers, contribute effectively for the carrier detection in hemophilia. Due to the large size of FVIII gene (∼186 Kb), direct mutation analysis is not handy. Therefore, linkage analysis using informative markers has been considered as the pragmatic approach where the propositus, his heterozygous mother, and suspected carrier are available. For the better assessment of carriership, haplotypes of various genomic markers have obvious advantage over the determination of allelic frequencies of individual polymorphisms. This review examines the existing repertoire of useful markers, current advancements and trail along the feasibility of using haplotypes and linkage disequilibrium strategies for the indirect genetic analysis in the direction of efficient carrier testing.

Keywords

factor VIII gene, haplotypes, linkage disequilibrium, indirect genetic analysis, carrier detection, preimplantation genetic haplotyping