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Systematic molecular analysis of hemophilia A patients from Colombia.

ABSTRACT: Hemophilia A (HA) is an X-linked recessive disorder and the second most common coagulation disorder with an incidence of 1 in 5,000 live born males. Worldwide, there are 178,500 affected individuals, 60% with the severe form of the disease. Intron 22 and 1 inversions (Inv22 and Inv1) are the most frequent molecular alterations found in severe HA patients with a frequency of 45-50% and 0.5-5%, respectively. We have implemented a systematic cost-effective strategy for the identification of the molecular alteration in HA patients using Inverse shifting-PCR for Inv22 and Inv1, followed by the analysis of the F8 gene coding region by means of high resolution melting (HRM) PCR and Sanger sequencing in Inv22 and Inv1 negative patients. A total of 33 male HA patients and 6 women were analyzed. Inversion 22 was detected in 14/33 male patients (42.4%), 3/33 (9.1%) had Inv1, 3/33 (9.1%) had large structural variants, and 11/33 (33.3%) single nucleotide/ small frameshift variants. No genetic variant was found in 2/33 patients (6%). With this systematic approach we detected pathogenic variants in 31 out of 33 male affected individuals (94%) tested for the first time.in a cohort of patients from Colombia.

SUBMITTER: Yunis LK

PROVIDER: S-EPMC6415612 | biostudies-literature | 2018 Oct-Dec

REPOSITORIES: biostudies-literature

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Systematic molecular analysis of hemophilia A patients from Colombia.

Yunis Luz Karime LK Linares Adriana A Cabrera Edgar E Yunis Juan J JJ

Genetics and molecular biology 20181001 4

Hemophilia A (HA) is an X-linked recessive disorder and the second most common coagulation disorder with an incidence of 1 in 5,000 live born males. Worldwide, there are 178,500 affected individuals, 60% with the severe form of the disease. Intron 22 and 1 inversions (Inv22 and Inv1) are the most frequent molecular alterations found in severe HA patients with a frequency of 45-50% and 0.5-5%, respectively. We have implemented a systematic cost-effective strategy for the identification of the mol ...[more]

PMID: 30534853

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Project description:BackgroundDifferent prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making.ObjectiveTo compare the effects of factor replacement therapies in patients with hemophilia.MethodsWe performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857).ResultsNine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration.ConclusionsOur results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.

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Systematic molecular analysis of hemophilia A patients from Colombia.

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Systematic molecular analysis of hemophilia A patients from Colombia.

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