Genetic testing in bleeding disorders

Abstract

Summary The aim of molecular genetic analysis in families with haemophilia is to identify the causative mutation in an affected male as this provides valuable information for the patient and his relatives. For the patient, mutation identification may highlight inhibitor development risk or discrepancy between different factor VIII assays. For female relatives, knowledge of the familial mutation can facilitate carrier status determination and prenatal diagnosis. Recent advances in understanding mutations responsible for haemophilia and methods for their detection are presented. For reporting of such mutations, participation in external quality assessment ensures that essential patient and mutation details are routinely included and that pertinent information is incorporated in the interpretation.

Accurate, simple, and inexpensive assays to diagnose F8 gene inversion mutations in hemophilia A patients and carriers

“…Genotyping of hemophilia patients and family members (ie, determining the hemophilia-causing mutation) is important to patients and their families, as well as to physicians who provide their clinical care. 19,20 Genotyping can aid in clinical management by predicting the potential severity of the bleeding disorder and by indicating (albeit with less accuracy) the relative risk that patients may develop neutralizing anti-factor VIII antibodies. 21 Because most HA carriers possess both a normal and a mutated X chromosome, these carriers have a 50% chance of transmitting the mutated copy to their children.…”

Identification of mutations in theF8andF9gene in families with haemophilia using targeted high‐throughput sequencing

“…Haemophilia A (HA) and haemophilia B (HB) are two forms of sex‐linked monogenic hereditary disorder caused by mutation of the coagulation factor VIII ( F8 ) and IX ( F9 ) gene, respectively . HA affects approximately 1 in 5000 males and HB affects about 1 in 25 000 males worldwide . To date, 2015 unique variants have been documented on the Factor VIII (FVIII) variant database (http://www.factorviii-db.org/) and 1095 variants in the Factor IX (FIX) Variant Database (http://www.factorix.org/).…”

Management of Inherited Bleeding Disorders in Pregnancy

“…3 Up to 50% of haemophilia cases have no previous family history, either owing to lack of male relatives or spontaneous mutation, which occurs in 40-50% of cases of severe haemophilia. Spontaneous mutations occur more commonly during spermatogenesis than oogenesis because of the high cell turnover and unpaired X chromosome.…”

“…Haemophilia is an X-linked bleeding disorder caused by a genetic mutation in either factor VIII (haemophilia A) or factor IX (haemophilia B) which causes absent or reduced production of that coagulation factor. [1][2][3] The hallmark of the condition is bleeding into joints and muscles.…”