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Informativeness of a novel multiallelic marker‐set comprising an F8 intron 21 and three tightly linked loci for haemophilia A carriership analysis
Author(s) -
MACHADO F. B.,
ALVES DA SILVA A. F.,
ROSSETTI L. C.,
DE BRASI C. D.,
MEDINAACOSTA E.
Publication year - 2011
Publication title -
haemophilia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.213
H-Index - 92
eISSN - 1365-2516
pISSN - 1351-8216
DOI - 10.1111/j.1365-2516.2010.02404.x
Subject(s) - genetics , linkage disequilibrium , intron , biology , loss of heterozygosity , gene , haplotype , compound heterozygosity , genetic linkage , allele
Summary. The extraordinary heterogeneous nature of the deleterious mutations in the F8 gene that lead to functional deficiency of clotting factor VIII in haemophilia A makes routine direct mutation profiling difficult. When direct mutation analysis cannot be performed or a causative/candidate mutation is not found, a second‐line approach to track the defective F8 gene within at‐risk families is linkage genetic analysis with, tried‐and‐tested, F8 ‐intragenic and/or extragenic non‐recombining multiallelic short tandem repeats (STR). Although several typing STR loci within and around F8 have been described, there is need for improving assessment, because the combined informativeness of available assays rarely reaches 100%. Here, we characterized a newly identified 0.28 cM‐resolution marker‐set, consisting of a dinucleotide STR located on F8 intron 21 ( F8 Int21; [AC] n ) and three extragenic tetranucleotide STR located on GAB3 intron 1 ( GAB3 Int1; [TAAA] n ) and TMLHE intron 1 ( TMLHE Int1.1; [GAAA] n and TMLHE Int1.3; [ATTC] n ). Heterozygosity rates determined in 100 unrelated females ranged from 0.25 ( GAB3 Int1) to 0.63 ( F8 Int21). The set rendered a combined informativeness of 0.91 for at least one marker and 0.60 for a minimum of two loci, with at least one F8 ‐intragenic. Multiallelic interlocus non‐random association analysis revealed that GAB3 Int1 is not in significant gametic disequilibrium (GD) with F8 Int21, F8 Int9.2, TMLHE Int1.3 or TMLHE Int1.1. Gametic disequilibrium breakdown attests historical recombination between GAB3 Int1 and the F8 gene. Through computational analysis of reference assembly sequence data, we note in the GD breakdown region and in the F8 gene a higher than average density of the 13‐mer CCNCCNTNNCCNC consensus motif, commonly associated with recombination hotspots.