In Autosomal Dominant Inheritance Cgi Path
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In Autosomal Dominant Inheritance Cgi Path
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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS |
March 15, 2001
1 From the Department of Internal Medicine, University of Texas–Houston Medical School, Houston, TX, and Centeon L.L.C., King of Prussia, PA.
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1 From the Department of Internal Medicine, University of Texas–Houston Medical School, Houston, TX, and Centeon L.L.C., King of Prussia, PA.
Search for other works by this author on:
1 From the Department of Internal Medicine, University of Texas–Houston Medical School, Houston, TX, and Centeon L.L.C., King of Prussia, PA.
Search for other works by this author on:
1 From the Department of Internal Medicine, University of Texas–Houston Medical School, Houston, TX, and Centeon L.L.C., King of Prussia, PA.
Search for other works by this author on:
1 From the Department of Internal Medicine, University of Texas–Houston Medical School, Houston, TX, and Centeon L.L.C., King of Prussia, PA.
Search for other works by this author on:
1 From the Department of Internal Medicine, University of Texas–Houston Medical School, Houston, TX, and Centeon L.L.C., King of Prussia, PA.
Search for other works by this author on:
1 From the Department of Internal Medicine, University of Texas–Houston Medical School, Houston, TX, and Centeon L.L.C., King of Prussia, PA.
Search for other works by this author on:
https://doi.org/10.1182/blood.V97.6.1549
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The rare inherited coagulation disorders: a review.
Parahaemophilia, haemorrhagic diathesis due to absence of a previously unknown clotting factor.
The use of the dilute Russell viper venom time for the diagnosis of lupus anticoagulants.
Whitehead Institute for Biomedical Research/MIT Center for Genome Research, http://www-genome.wi.mit.edu Accessed May 5, 1998.
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Trinucleotide repeat polymorphism in the human antithrombin III (AT3) gene.
A 10-cM YAC contig spanning GLC1A, the primary open-angle glaucoma locus at 1q23–q25.
Recombinational and physical mapping of the locus for primary open-angle glaucoma (GLC1A) on chromosome 1q23–q25.
Fine mapping of the autosomal dominant juvenile open angle glaucoma (GLC1A) region and evaluation of candidate genes.
A gene for familial paroxysmal dyskinesia (FPD1) maps to chromosome 2q.
Severe coagulation factor V deficiency caused by a 4 bp deletion in the factor V gene.
Isolation and sequence characterization of a cDNA clone of human antithrombin III.
Molecular genetics of human antithrombin III deficiency.
Structure of the gene for human coagulation factor V.
Cloning of cDNAs coding for the heavy chain region and connecting region of human factor V, a blood coagulation factor with four types of internal repeats.
Strategies for multilocus linkage analysis in humans.
Faster sequential genetic linkage computations.
Avoiding recomputation in linkage analysis.
Multilocus linkage analysis in humans: detection of linkage and estimation of recombination.
Location on the human genetic linkage map of 26 genes involved in blood coagulation.
A comprehensive genetic map of the human genome based on 5264 microsatellites.
Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness.
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Copyright © 2001 The American Society of Hematology
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Shao-Qing Kuang, Sumera Hasham, Martin D. Phillips, David Wolf, Ying Wan, Perumal Thiagarajan, Dianna M. Milewicz; Characterization of a novel autosomal dominant bleeding disorder in a large kindred from east Texas. Blood 2001; 97 (6): 1549–1554. doi: https://doi.org/10.1182/blood.V97.6.1549
A large east Texas family with autosomal dominant inheritance of a novel bleeding disorder has been identified. The disorder is characterized clinically by easy bruising, life-threatening bleeding with trauma or surgery, and menorrhagia in affected women. Laboratory studies demonstrated prolongation of the prothrombin time and activated partial thromboplastin time in affected individuals. Paradoxically, assays of known coagulation factors are all within normal limits. To determine the molecular basis of this disease, a candidate gene linkage analysis in this kindred was done. Initially it was hypothesized that the cause of the disease in this family could be an antithrombin III (AT3) mutation that resulted in a constitutively active AT3 in the absence of heparin binding. Linkage studies using DNA from the family and an intragenic polymorphic marker within the AT3 gene showed that the disease mapped to this locus. The coding region and intron/exon junctions of AT3 were sequenced using the proband's DNA, but this analysis failed to identify a mutation. Additional family members were recruited for the study, and 16 polymorphic markers around the AT3 gene were analyzed. Using 2 recombinants, the critical interval for the defective gene was narrowed to approximately 1.5 Mb, centromeric to AT3 . The factor V (FV) gene was mapped into the disease interval and sequenced; there were no mutations found. Elucidation of the genetic defect causing the bleeding disorder in this family may reveal a novel protein involved in the coagulation cascade.
Inherited bleeding disorders have a variety of etiologies including impaired function of platelets, blood vessels, blood coagulation pathways, the anticoagulant pathways, or the fibrinolytic system. The clinical manifestations and laboratory findings of this phenotype vary greatly between and within families. The severity of the underlying protein defect often determines the clinical presentation of affected patients, and bleeding may vary from spontaneous hemorrhage to significant bleed loss following surgery or physical trauma. Hemophilia A, hemophilia B, and von Willebrand disease (vWD) comprise more than 80% of all inherited bleeding disorders. 1-4
A large kindred from east Texas has been identified with a novel bleeding disorder that is inherited in an autosomal dominant manner. The bleeding disorder is moderate in severity and characterized by a prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) and normal levels of all known coagulation factors. The disorder has been mapped to a 1.47-Mb region at chromosome 1q23, and known candidate genes at this location have been excluded as the cause of the disease in this family. Identification of the defective gene causing this disorder may identify a previously unrecognized protein involved in the coagulation cascade and further expand our knowledge about the proteins involved in this system.
We studied a Texas family of 4 generations with 46 members (Figure 1 ). The proband (III:10) was a 35-year-old man with a bleeding diathesis since childhood characterized by bruising, epistaxis, bleeding from gums, and significant bleeding after minor trauma, but no hemarthrosis or spontaneous hematomas. The proband required 2 blood transfusions as a child: at the age of 2 years, after sustaining a laceration from a fall, and at 12 years, following a tooth extraction. The PT was 18.4 seconds (normal range, 11.1-13.1 seconds), and the aPTT was 48.7 seconds (normal range, 25-34 seconds) (Table 1 ). There was a modest variability of these assays from day to day. The following studies were all normal: thrombin time, functional fibrinogen level, von Willebrand antigen and ristocetin cofactor, bleeding time, and platelet number and aggregation. The following factor activity levels were normal: II, V, VII, VIII, IX, X, XI, and XII. Factor V and X levels were the same, with serial dilutions up to 1:16, and the dilution curves were parallel to the standard curve. The protein C activity and resistance ratio was normal. Mixing studies were performed to detect a circulating inhibitor (Table 2 ).
Pedigree of the family with the inherited bleeding disorder.
Closed symbol indicates affected; open symbol, unaffected; and open symbol with ?, disease status unknown. The PT and aPTT are indicated after the generation and family number; ND indicates not determined. Genetic haplotypes are indicated for all individuals who were genotyped. The filled black bar indicates the haplotype cosegregating with the disease. Recombinations are indicated by open bars.
Pedigree of the family with the inherited bleeding disorder.
Closed symbol indicates affected; open symbol, unaffected; and open symbol with ?, disease status unknown. The PT and aPTT are indicated after the generation and family number; ND indicates not determined. Genetic haplotypes are indicated for all individuals who were genotyped. The filled black bar indicates the haplotype cosegregating with the disease. Recombinations are indicated by open bars.
Laboratory evaluation of the proband
PT indicates prothrombin time; aPTT, activated partial thromboplastin time, AT3, antithrombin III; vWF, von Willebrand factor; RVVT, Russell viper venom time.
Various concentrations of patient's plasma mixed with control plasma and the clotting times determined immediately and one hour later
aPTT indicates activated partial thromboplastin time.
The proband's sister (III:18) also had bleeding problems including easy bruising and menorrahagia. As a child she had excessive bleeding with shedding of her baby teeth, which required packing with gauze. At the age of 7 years, 3 days following a tonsillectomy, she had an onset of bleeding that required an infusion of 2 units of blood and 2 units of plasma. Excessive bleeding also occurred with the removal of an ingrown toenail and a tooth extraction, but no transfusions were required. At 15 years, she was operated on for possible appendicitis and was found to have a right hemorrhagic ovarian cyst. She received a blood transfusion postoperatively. Her PT was prolonged at 13.7 seconds (normal range, 9.5-12 seconds), and her aPTT was prolonged at 51.1 seconds (normal range, 29-39 seconds), but all factor assays, thrombin time, functional fibrinogen level, von Willebrand antigen and ristocetin cofactor, bleeding time, and platelet number and aggregation were normal. At 18 years she underwent labor and delivery without bleeding complications. At 19 years she was again hospitalized for ovarian cystic hemorrhage, but did not require a transfusion.
The proband's brother (III:12) had epistaxis, bleeding gums during tooth brushing, and easy bruising, but no other problems. His PT and aPTT were prolonged (Figure 1 ). Another sister of the proband (III:20) had recurrent episodes of epistaxis and bleeding that began during her childhood. She had an appendectomy and gave birth to her first child without bleeding complications. Delivery of her second child was complicated by excessive bleeding, and she required a blood transfusion.
Other members of the family were clinically assessed, and the PT and aPTT were determined (Figure 1 ). For the purpose of this study, affected members were defined by the presence of clinical manifestations of the bleeding disorder and either a mild or moderately prolonged PT and/or aPTT. The clinical features of the bleeding disorder include severe postsurgical bleeding and easy bruising, and affected women also experienced menorrhagia.
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