F8 gene mutation profile in Indian hemophilia A patients: Identification of 23 novel mutations and factor VIII inhibitor risk association

Pinto, Paulo Daniel Araújo; Ghosh, Kanjaksha; Shetty, Shrimati

doi:10.1016/j.mrfmmm.2016.02.002

Cited by 11 publications

(17 citation statements)

References 22 publications

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“…in 24 out of 50 haemophilia A patients. The mutations detected were not unlike those reported from India, although yields have been higher in Indian studies [2]: 22 of the Iranian cases had the intron 22 inversion, while one each had intron 1 inversion and a point mutation in exon 14. The study highlights the challenges and limitations of conventional testing strategies for the diagnosis of inherited bleeding disorders and the geographical variability.…”

contrasting

confidence: 53%

“…Less commonly, molecular tools may be applied for the distinction of phenocopies (i.e. type 2 vWD from platelet-type vWD, or moderate haemophilia A from type 2N vWD) or sometimes to obtain clinically relevant genetic information, like haemophilia mutationbased inhibitor risk profiling [2] or to confirm F9 promoter mutations causing haemophilia B Leyden [5] for prognostication.…”

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confidence: 99%

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Molecular Genetic Diagnosis of the Inherited Bleeding Disorders: Are We Close to the Perfect Test?

Pati¹,

Sharma²

2016

Indian J Hematol Blood Transfus

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contrasting

confidence: 53%

mentioning

confidence: 99%

Molecular Genetic Diagnosis of the Inherited Bleeding Disorders: Are We Close to the Perfect Test?

Pati¹,

Sharma²

2016

Indian J Hematol Blood Transfus

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“…B). In Indian and Iranian patients, representing 35% and 13% of our cases, the mutation distribution was similar to those in previous reports from those countries .…”

Section: Resultsmentioning

confidence: 99%

Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement

Spena

Garagiola

Cannavó

et al. 2018

Journal of Thrombosis and Haemostasis

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Background The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow residual synthesis of factor VIII are likely to play a protective role against alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. Objectives To explore the mutation type-inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) randomized trial. Methods The genetic defects in these patients, consisting of inversions of intron 22 (n = 110) and intron 1 (n = 6), large deletions (n = 16), and nonsense (n = 38), frameshift (n = 28), missense (n = 19) and splicing (n = 14) variants, of which 34 have been previously unreported, were reclassified according to two additional criteria: the functional effects of missense and splicing alterations as predicted by multiple in silico analyses, and the levels of FVIII antigen in patient plasma. Results A two-fold increase in inhibitor development for in silico null mutations as compared with in silico non-null mutations (hazard ratio [HR] 2.08, 95% confidence interval [CI] 0.84-5.17) and a 3.5-fold increase in inhibitor development for antigen-negative mutations as compared with antigen-positive mutations (HR 3.61, 95% CI 0.89-14.74] were found. Conclusions Our findings confirm an association between the synthesis of minute amounts of FVIII and inhibitor protection, and underline the importance of investigating the residual FVIII antigen levels associated with causative variants in order to understand their clinical relevance.

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“…Deletions, insertions and point mutations account for the remaining 50-60% of the F8C defects that cause hemophilia A. 29 FVIII deficiency, dysfunctional FVIII, or FVIII inhibitors lead to the disruption of the normal intrinsic coagulation cascade, resulting in excessive hemorrhage in response to trauma and, in severe cases, spontaneous hemorrhage. Hemorrhage sites include joints (e.g., knee, elbow); muscles; the central nervous system; and the gastrointestinal, genitourinary, pulmonary, and cardiovascular systems.…”

Section: Discussionmentioning

confidence: 99%

A hemophilic patient presented with an abdominal mass, fever and cough

Rahman

Khan

Islam

et al. 2018

Bangabandhu Sheikh Mujib Medical University Journal

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F8 gene mutation profile in Indian hemophilia A patients: Identification of 23 novel mutations and factor VIII inhibitor risk association

Cited by 11 publications

References 22 publications

Molecular Genetic Diagnosis of the Inherited Bleeding Disorders: Are We Close to the Perfect Test?

Molecular Genetic Diagnosis of the Inherited Bleeding Disorders: Are We Close to the Perfect Test?

Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement

A hemophilic patient presented with an abdominal mass, fever and cough

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