title: F8 gene mutation profile in Indian hemophilia A patients: Identification of 23 novel mutations and factor VIII inhibitor risk association.
abstract: 'FVIII inhibitors', especially in severe hemophilia A (HA) patients, is a serious adverse effect that complicates their clinical management. Many genetic and non-genetic risk factors have been proposed for FVIII inhibitor development, diverse in different population groups. This is the first study in Indian hemophiliacs that analyzes inhibitor risk in relation to the complete F8 mutation profile, in a case-control study that included 145 Indian severe HA patients, i.e. 69 inhibitor positive (with 18 inhibitor concordant/discordant family members), and 58 inhibitor negative patients, after informed consent. While 53.54% (68/127) index cases were positive for intron 22 or intron 1 inversions, 55 causative F8 mutations were detected in the 59 inversion negative patients, of which 23 were novel mutations (in 24 patients) and 32 were reported earlier (in 35 patients). A higher incidence of mutations, in the C1 and C2 domains in inhibitor positive patients, and in the A1 domain in inhibitor negative patients was observed, though not significantly different. The study suggests that large F8 rearrangements (significantly higher in the inhibitor positive patients) pose the highest risk, while missense mutations (significantly higher in the inhibitor negative patients) pose the lowest risk of inhibitor development in Indian hemophilia A patients.
authors.affiliation: National Institute of Immunohaematology (ICMR), 13th Floor, New Multistoreyed Building, KEM Hospital Campus, Parel, Mumbai 400 012, India.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pinto
authors.affiliation: National Institute of Immunohaematology (ICMR), 13th Floor, New Multistoreyed Building, KEM Hospital Campus, Parel, Mumbai 400 012, India.
authors.forename: Kanjaksha
authors.initials: K
authors.lastname: Ghosh
authors.affiliation: National Institute of Immunohaematology (ICMR), 13th Floor, New Multistoreyed Building, KEM Hospital Campus, Parel, Mumbai 400 012, India. Electronic address: shrimatishetty@yahoo.com.
authors.forename: Shrimati
authors.initials: S
authors.lastname: Shetty
mesh_terms: D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015321:Gene Rearrangement; D060005:Genotyping Techniques; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D007194:India; D007438:Introns; D008297:Male; D020125:Mutation, Missense; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics*
chemical_list: D005169:Factor VIII
keywords: F8 mutations; FVIII inhibitors; Hemophilia A; Risk factors