Evaluation of factor VIII polymorphic short tandem repeat markers in linkage analysis for carrier diagnosis of hemophilia A

Abstract

Abstract. Hemophilia A (HA) is the most common inherited X-linked recessive bleeding disorder caused by heterogeneous mutations in the factor VIII gene (FVIII). Diagnosis of the carrier is critical for preventing the birth of children affected by this coagulation disorder, which ultimately facilitates its management. Due to the heterogeneous nature of mutations, the large inversions and the complexity of the FVIII gene, direct recognition of the disease-associated mutation in HA is complex. Indirect linkage analysis using highly informative heterozygous polymorphic markers is an alternative method for determining the co-segregation of the mutant gene within a family for carrier detection of HA. The aim of the present study was to perform carrier diagnosis in a family with HA. Rapid multifluorescent polymerase chain reaction (PCR) was performed with six extragenic short tandem repeats (STRs), DXS1073, DXS15, DXS8091, DXS1227, DXS991, DXS993 and one intragenic marker, STR22 for linkage analysis in the HA family. All the STR markers employed in the present study were informative for linkages of pathogenic and healthy haplotypes among family members, particularly STR22, DXS1073 and DXS15. The STR marker, STR22, is within the FVIII gene while the DXS1073 and DXS15 markers are very close to the FVIII gene, where the chances of recombination are comparatively low, and provided the most accurate interpretation analysis, indicating that the proband's sister may have been the HA carrier. Rapid multifluorescent PCR using STR markers and linkage analysis was identified to be a simple method for performing HA carrier diagnosis.

Genetic analysis for carrier diagnosis in hemophilia A and B in the Mexican population: 25 years of experience

“…It is also difficult to develop this approach due to the large size of the F8 gene and the pathogenic variantal heterogeneity in HA. Therefore, we performed the linkage analysis of intragenic neutral variants of F8 gene for a rapid and economical carrier diagnosis strategy (Shrestha, Dong, Li, Huang, & Zheng, 2016).…”

Development and validation of a novel panel of 16 STR markers for simultaneous diagnosis of β-thalassemia, aneuploidy screening, maternal cell contamination detection and fetal sample authenticity in PND and PGD/PGS cases

“…We showed that using STR markers can be very helpful in several ways for performing either PGDs 35 or in special cases of PNDs where hematological indices indicate that the parents are carrier/s of β-thal 36 , even when no mutation can be found using techniques like whole gene sequencing or MLPA 37 . In addition, haplotype analysis can be helpful when there is a time constraint to find the mutation and even confirming direct mutation analysis findings 38 .…”