title: Analysis of factor VIII gene inversion mutations in 166 unrelated haemophilia A families: frequency and utility in genetic counselling.
abstract: Haemophilia A is an X-linked recessive bleeding disorder of variable severity that is caused by a deficiency of coagulation factor VIII (FVIII). The disease results from mutations in the FVIII gene which are heterogenous both in type and position within the gene. Recently, however, inversion mutations were found to be common to patients with severe disease (Lakich et al., 1993). These mutations result from intrachromosomal recombinations between DNA sequences in the A gene (located in intron 22 of the FVIII gene) and one of two A genes upstream to the FVIII gene. To determine the frequency of these inversions we performed Southern blot analysis on banked DNA from 166 consecutive, unrelated haemophilia A families previously referred for carrier or prenatal testing. In 57/166 (34%) families an inversion or other unique mutation was detected. The distal and proximal A genes lying upstream to the FVIII gene were involved in 79% and 18% of the mutations, respectively, but in 3% of the families the sequences involved in the mutation have not been identified. In 20/38 (53%) families with severe disease a mutation was detected. Interestingly, the relative risk of developing inhibitors in patients with FVIII gene inversions or other 3° mutations detected by this assay, as compared to patients with no detectable mutation by this assay, was 3.8. In families for which a mutation is detected, direct DNA testing is an accurate and inexpensive alternative to linkage analysis for prenatal or haemophilia A carrier testing.
authors.affiliation: Departments of Pathology, Pediatrics, and Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, and Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Cindy L. Vnencak-Jones, Ph.D., Associate Professor of Pathology and Pediatrics, Department of Pathology, Vanderbilt University Medical Center, 4605 TVC, Nashville, TN 37232, USA.*John A. Phillips III, M.D., Professor of Pediatrics and Biochemistry, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Robert L. Janco, M.D., Associate Professor of Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Melinda P. Cohen, M.S., Assistant in Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.William D. Dupont, Ph.D., Professor of Preventive Medicine, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Haig H. Kazazian, M.D., Professor of Genetics, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.Judith P. Rossiter, M.D., Assistant Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Vnencak-Jones
authors.affiliation: Departments of Pathology, Pediatrics, and Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, and Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Cindy L. Vnencak-Jones, Ph.D., Associate Professor of Pathology and Pediatrics, Department of Pathology, Vanderbilt University Medical Center, 4605 TVC, Nashville, TN 37232, USA.*John A. Phillips III, M.D., Professor of Pediatrics and Biochemistry, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Robert L. Janco, M.D., Associate Professor of Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Melinda P. Cohen, M.S., Assistant in Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.William D. Dupont, Ph.D., Professor of Preventive Medicine, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Haig H. Kazazian, M.D., Professor of Genetics, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.Judith P. Rossiter, M.D., Assistant Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: John
authors.initials: J
authors.lastname: Phillips
authors.affiliation: Departments of Pathology, Pediatrics, and Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, and Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Cindy L. Vnencak-Jones, Ph.D., Associate Professor of Pathology and Pediatrics, Department of Pathology, Vanderbilt University Medical Center, 4605 TVC, Nashville, TN 37232, USA.*John A. Phillips III, M.D., Professor of Pediatrics and Biochemistry, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Robert L. Janco, M.D., Associate Professor of Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Melinda P. Cohen, M.S., Assistant in Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.William D. Dupont, Ph.D., Professor of Preventive Medicine, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Haig H. Kazazian, M.D., Professor of Genetics, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.Judith P. Rossiter, M.D., Assistant Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Janco
authors.affiliation: Departments of Pathology, Pediatrics, and Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, and Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Cindy L. Vnencak-Jones, Ph.D., Associate Professor of Pathology and Pediatrics, Department of Pathology, Vanderbilt University Medical Center, 4605 TVC, Nashville, TN 37232, USA.*John A. Phillips III, M.D., Professor of Pediatrics and Biochemistry, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Robert L. Janco, M.D., Associate Professor of Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Melinda P. Cohen, M.S., Assistant in Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.William D. Dupont, Ph.D., Professor of Preventive Medicine, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Haig H. Kazazian, M.D., Professor of Genetics, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.Judith P. Rossiter, M.D., Assistant Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Cohen
authors.affiliation: Departments of Pathology, Pediatrics, and Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, and Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Cindy L. Vnencak-Jones, Ph.D., Associate Professor of Pathology and Pediatrics, Department of Pathology, Vanderbilt University Medical Center, 4605 TVC, Nashville, TN 37232, USA.*John A. Phillips III, M.D., Professor of Pediatrics and Biochemistry, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Robert L. Janco, M.D., Associate Professor of Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Melinda P. Cohen, M.S., Assistant in Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.William D. Dupont, Ph.D., Professor of Preventive Medicine, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Haig H. Kazazian, M.D., Professor of Genetics, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.Judith P. Rossiter, M.D., Assistant Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: W D
authors.initials: WD
authors.lastname: Dupont
authors.affiliation: Departments of Pathology, Pediatrics, and Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, and Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Cindy L. Vnencak-Jones, Ph.D., Associate Professor of Pathology and Pediatrics, Department of Pathology, Vanderbilt University Medical Center, 4605 TVC, Nashville, TN 37232, USA.*John A. Phillips III, M.D., Professor of Pediatrics and Biochemistry, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Robert L. Janco, M.D., Associate Professor of Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Melinda P. Cohen, M.S., Assistant in Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.William D. Dupont, Ph.D., Professor of Preventive Medicine, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Haig H. Kazazian, M.D., Professor of Genetics, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.Judith P. Rossiter, M.D., Assistant Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Kazazian
authors.affiliation: Departments of Pathology, Pediatrics, and Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, and Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Cindy L. Vnencak-Jones, Ph.D., Associate Professor of Pathology and Pediatrics, Department of Pathology, Vanderbilt University Medical Center, 4605 TVC, Nashville, TN 37232, USA.*John A. Phillips III, M.D., Professor of Pediatrics and Biochemistry, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Robert L. Janco, M.D., Associate Professor of Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Melinda P. Cohen, M.S., Assistant in Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.William D. Dupont, Ph.D., Professor of Preventive Medicine, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.Haig H. Kazazian, M.D., Professor of Genetics, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.Judith P. Rossiter, M.D., Assistant Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Rossiter
keywords: direct DNA testing; factor VIII inhibitors; genetic counselling; haemophilia A; inversion mutations; severe disease