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Journal articles on the topic 'Hemophilia – Genetics'

Author: Grafiati

Published: 30 June 2021

Last updated: 10 February 2022

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1

Knox, David, Christopher Samuel, Janneth Pazmino-Canizares, Chris Barnes, Georgina Floros, Ann Marie Stain, and Manuel Carcao. "The Genetics of Hemophilia: Analysis of Patients at the Hospital for Sick Children, Toronto, Canada." Blood 108, no. 11 (November 16, 2006): 1040. http://dx.doi.org/10.1182/blood.v108.11.1040.1040.

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Abstract There is great interest in identifying genetic mutations responsible for hemophilia and in determining if/how mutations correlate with disease phenotype. A hemophilia genetic database was created at SickKids in 2004. At the time <40% of hemophiliacs followed by the clinic had been genotyped. Currently mutations have been identified on 194/236 patients (82%) followed in the clinic. From this we are performing genotype/phenotype correlations. Preliminary analysis has revealed the following novel findings: Most mothers of hemophiliacs are carriers; even when there is a no family history of hemophilia. Of the 199 mothers of the 236 children only 6 have been shown not to be carriers; 205 have been shown to be carriers; 15 have not been tested and 10 are unavailable for testing. We believe that most de novo FIX and FVIII mutations occur in females. Mutations responsible for hemophilia B show poor concordance with disease severity i.e. for any mutation the disease severity is not always the same. One example found in 10 hemophiliacs (5 families) who despite having the same missense mutation in exon H have shown FIX levels anywhere between 0 and 11%. Given that disease severity is assigned according to factor levels these patients have been labeled as either severe (n = 3), moderate (n = 5) or mild (n = 2). Clinically these patients all appear to behave as moderate. This points to the fallibility of using FIX levels (which varies according to patient age and health state) in labeling patients. Other aspects of the hemophilia genetic data base are being analyzed. We believe that a detailed study of the genetics of hemophilia will point to novel findings that will eventually translate into patient care.

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2

Lawn, Richard M., and Gordon A. Vehar. "The Molecular Genetics of Hemophilia." Scientific American 254, no. 3 (March 1986): 48–54. http://dx.doi.org/10.1038/scientificamerican0386-48.

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3

Geddes, Valerie A., and Ross T. A. MacGillivray. "The Molecular Genetics of Hemophilia B." Transfusion Medicine Reviews 1, no. 3 (December 1987): 161–70. http://dx.doi.org/10.1016/s0887-7963(87)70018-2.

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4

Chudley, Albert E., and James C. Haworth. "Genetic landmarks through philately - hemophilia." Clinical Genetics 56, no. 4 (October 1999): 279–81. http://dx.doi.org/10.1034/j.1399-0004.1999.560404.x.

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5

Gouw, Samantha C., and Karin Fijnvandraat. "Unraveling the genetics of inhibitors in hemophilia." Blood 121, no. 8 (February 21, 2013): 1250–51. http://dx.doi.org/10.1182/blood-2012-12-472647.

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6

Tantawy, Azza A. G. "Molecular genetics of hemophilia A: Clinical perspectives." Egyptian Journal of Medical Human Genetics 11, no. 2 (November 2010): 105–14. http://dx.doi.org/10.1016/j.ejmhg.2010.10.005.

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7

Astermark, Jan, John Schwarz, Sharyne M. Donfield, Donna M. DiMichele, Bruce M. Ewenstein, Edward D. Gomperts, George W. Nelson, et al. "Genetic Factors Associated with Inhibitor Development in Hemophilia A: Initial Results From the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort." Blood 114, no. 22 (November 20, 2009): 217. http://dx.doi.org/10.1182/blood.v114.22.217.217.

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Abstract Abstract 217 Introduction: Both genetic and environmental factors have been implicated as potential risk factors for the development of inhibitory factor VIII (FVIII) antibodies. Previous studies suggest that genetic factors are of major importance. The causative FVIII mutation likely sets the stage for inhibitor risk, with other genetic markers important in determining the final outcome. Data suggest that the process of inhibitor development is complex, involving a variety of immune regulatory genes, several of which have the potential to modify risk. Through a collaboration among three multi-center studies: the Hemophilia Inhibitor Genetics Study (HIGS), the Malmö International Brother Study (MIBS), and the Hemophilia Growth and Development Study (HGDS), a combined cohort was formed to conduct an association study to test the hypothesis that antibody development to FVIII is mediated by immune response genes. Methods: The study includes clinical and laboratory data for 680 people with hemophilia A. Participants from Europe and North America account for 43% and 57% of the population, respectively. Eighty-five percent have severe (<0.01 IU/mL), 10% moderate (0.01 – 0.05% IU/mL), and 4.4% mild (>0.05 – 0.4 IU/mL) hemophilia. The cohort is predominately Caucasian, 81.0%, with 6.2% of African heritage, 8.8% Hispanic, and the remaining 4% of other races and ethnicities. Forty-nine percent have a current, or history of, an inhibitor ≥1 BU. Using the Illumina iSelect platform, 14,626 single nucleotide polymorphisms (SNPs) from 1,081 candidate genes were genotyped. These included immune response and immune modifier genes: cytokines and their receptors, chemokines and their receptors, and pathway genes involved in inflammatory and immune responses. Analyses were completed among the total group and the subgroup with severe hemophilia to identify SNPs associated with inhibitor status. The models were adjusted for population admixture, severity of hemophilia, type of mutation (high vs. low risk), year of birth, and geographic region. Meta analyses were used to obtain single odds ratios (OR) and p-values for the three cohorts. Results: 13,952 of the 14,626 (95.4%) SNPs were successfully genotyped. One hundred fourteen were associated with inhibitor status at the p<0.01 level. Strong SNP associations for the total group were observed in the DOCK2 (OR 0.28, p= 0.00004, and OR 3.9, p=0.0002), MAPK9 (OR 2.0, p=0.0003), F13A1 (OR 0.32, p=0.00007), CD36 (OR 0.56, p=0.0002), and PTPRR (OR 0.51, p=0.0003) genes. For four markers located within the MAPK9, DOCK2, and CD36 genes, the associations were similar, or stronger, for the subgroup with severe hemophilia. Analysis of polymorphisms in the FVIII gene, completion of HLA Class II typing, and haplotype analysis are underway. Conclusions: Our findings suggest that functional pathways involved in a variety of cellular processes will be important in inhibitor development, but these results warrant further study and replication in similarly powered case-control or cohort studies. Disclosures: Ewenstein: Baxter Healthcare: Employment. Spotts:Baxter Healthcare: Employment.

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8

Fernández, Raquel M., Ana Peciña, Beatriz Sánchez, Maria Dolores Lozano-Arana, Juan Carlos García-Lozano, Rosario Pérez-Garrido, Ramiro Núñez, Salud Borrego, and Guillermo Antiñolo. "Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/406096.

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Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD). Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B). Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%), constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders.

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9

Chuansumrit, Ampaiwan, Werasak Sasanakul, Ian Williams, Anne Goodeve, Praguywan Kadegasem, and Ian Peake. "Comparison of Phenotypic Assessment and Mutation Detection in the Diagnosis of Carrier State in Hemophilia: Identification of 10 Novel Mutations." Blood 104, no. 11 (November 16, 2004): 4020. http://dx.doi.org/10.1182/blood.v104.11.4020.4020.

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Abstract The carrier state in 54 females (A38, B16) at risk from 35 moderate and severe hemophilia families (A25, B10) in Thailand, was determined. They were classified as obligate (A17, B8) and possible (A21, B8) carriers by history taking. The phenotypic assessment was performed in two subsequent blood samples taken one week apart when they were not pregnant or on birth control pills. Then, molecular genetics among hemophiliac patients were performed. Inversion of intron 22 among 25 hemophilia A patients was initially performed. Then, the mutations were intensively detected by using conformation sensitive gel electrophoresis (CSGE). Coding region, intron/exon boun-daries, and 5′ and 3′ regions of the factor VIII and IX genes were amplified in 33 separate reactions in hemophilia A patients without inversion of intron 22 (n=10) and 9 separate reactions in hemophilia B patients (n=10). Samples displaying abnormal CSGE profiles were numbered according to Wood et al and Yoshitake et al. The results revealed that mutation were found at 88% (22/25, 15 inversion of intron 22 and 7 mutations) in hemophilia A and 90% (9/10) in hemophilia B patients. Ten were novel mutations as shown in Table 1. Also, the carrier state assessed by the phenotypic study and mutation detections are shown in Table 2. As a result, the phenotypic assessment alone showed a limitation in the diagnosis of carrier state especially hemophilia B carrier while the mutation detections provide an absolute diagnosis over phenotypic assessment. Table 1. The identified ten novel mutations among Thai hemophilia A and B patients. Table 2. Carrier state assessed by phenotypic study and mutation detections among females at risk. Exon Nucleotide Amino acid FVIII:C/FIX:C (%) Promotor to exon 22 large deletion - FVIII:C < 1 6 680 G>A W208X FVIII: C = 2 8 1264 G>C D403H FVIII:C < 1 12 1820_1821 del CA 588 frame shift FVIII:C < 1 13 2066 T>G L670R FVIII:C = 1 14 4794 A>T E1579D FVIII:C = 1 21 6266 G>A W2070X FVIII:C < 1 A 57_58 del GA −37 frame shift FIX:C < 1 H 31127 T>G C336G FIX:C < 1 H 31171 T>G C350W FIX:C = 3.6 Type of carrier N FVIII:C or FIX:C < 50% FVIII:C/vWF:Ag < 0.6 Inversion intron 22 CSGE Total mutation Obligate hemophilia A 17 35.3% 70.6% 64.7% 17.6% 82.3% Obligate hemophilia B 8 12.5% - - 87.5% 87.5% Possible hemophilia A 21 19.0% 42.8% 33.3% 14.3% 47.6% Possible hemophilia B 8 25.0% - - - 62.5%

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10

Kehl, Alexandra, Anita Haug Haaland, Ines Langbein-Detsch, and Elisabeth Mueller. "A SINE Insertion in F8 Gene Leads to Severe Form of Hemophilia A in a Family of Rhodesian Ridgebacks." Genes 12, no. 2 (January 21, 2021): 134. http://dx.doi.org/10.3390/genes12020134.

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Hemophilia A is the most common coagulation factor disorder in humans and dogs. The disease is characterized by the lack or diminished activity of Factor VIII (FVIII), caused by variants in the F8 gene and inherited as an X chromosomal trait. Two related male Rhodesian Ridgebacks were diagnosed with Hemophilia A due to reduced FVIII activity. The purpose of the study was to determine the genetic cause and give breeding advice for the remaining family members in order to eradicate the variant. By Sanger sequencing a short interspersed nuclear element (SINE) insertion in exon 14 of the F8 gene was found. Perfect correlation of this genetic variant with clinical signs of hemophilia A in the family tree, and the lack of this genetic variant in more than 500 unrelated dogs of the same and other breeds, confirms the hypothesis of this SINE being the underlying genetic cause of Hemophilia A in this family. The identification of clinically unaffected female carriers allows subsequent exclusion of these animals from breeding, to avoid future production of clinically affected male offspring and more subclinical female carriers.

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11

Guo, Xiao-Lu, Tsai-Hua Chung, Yue Qin, Jie Zheng, Huyong Zheng, Liyuan Sheng, Tung Wynn, and Lung-Ji Chang. "Hemophilia Gene Therapy: New Development from Bench to Bed Side." Current Gene Therapy 19, no. 4 (November 18, 2019): 264–73. http://dx.doi.org/10.2174/1566523219666190924121836.

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Novel gene therapy strategies have changed the prognosis of many inherited diseases in recent years. New development in genetic tools and study models has brought us closer to a complete cure for hemophilia. This review will address the latest gene therapy research in hemophilia A and B including gene therapy tools, genetic strategies and animal models. It also summarizes the results of recent clinical trials. Potential solutions are discussed regarding the current barriers in gene therapy for hemophilia.

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12

Ghosh, Kanjaksha, PreethiS Nair, and S. Shetty. "A homozygous female hemophilia A." Indian Journal of Human Genetics 18, no. 1 (2012): 134. http://dx.doi.org/10.4103/0971-6866.96685.

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13

Ginsburg, David. "Molecular Genetics of von Willebrand Disease." Thrombosis and Haemostasis 82, no. 08 (1999): 585–91. http://dx.doi.org/10.1055/s-0037-1615884.

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IntroductionVon Willebrand disease (vWD) is a common inherited bleeding disorder that is notable for a high degree of variability in clinical presentation and the considerable heterogeneity of its molecular basis. Confusion about the genetic origin of this disorder has existed since its original description by Eric von Willebrand in 1926.1 Dr. von Willebrand coined the term “pseudohemophilia” to describe the disease in the original pedigree. Though it resembled the bleeding diathesis of hemophilia, von Willebrand also noted findings suggesting an abnormality in platelet function. The severity of bleeding in this family varied widely from mild bleeding to severe hemorrhage, the latter resulting in the death of the proband at the time of her fourth menstrual period.Von Willebrand incorrectly characterized the inheritance pattern in the original Åland Island pedigree as X-linked dominant, because of the apparent greater frequency of the disease in female patients. Now, it is recognized that the greater frequency was largely by chance and due to increased penetrance related to the hemostatic stresses of menstruation and pregnancy. Nonetheless, von Willebrand clearly distinguished the inheritance pattern of vWD from that of classic hemophilia. It is now known that vWD is due to either quantitative or qualitative defects in von Willebrand factor (vWF), encoded by a gene on chromosome 12, whereas hemophilia is due to mutations in the factor VIII gene on the X chromosome.2

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14

Batty, Paul, and David Lillicrap. "Advances and challenges for hemophilia gene therapy." Human Molecular Genetics 28, R1 (July 23, 2019): R95—R101. http://dx.doi.org/10.1093/hmg/ddz157.

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Abstract Hemophilia is an X-linked inherited bleeding disorder, resulting from defects in the F8 (hemophilia A) or F9 (hemophilia B) genes. Persons with hemophilia have bleeding episodes into the soft tissues and joints, which are treated with self-infusion of factor VIII or IX concentrates. Hemophilia provides an attractive target for gene therapy studies, due to the monogenic nature of these disorders and easily measurable endpoints (factor levels and bleed rates). All successful, pre-clinical and clinical studies to date have utilized recombinant adeno-associated viral (AAV) vectors for factor VIII or IX hepatocyte transduction. Recent clinical data have presented normalization of factor levels in some patients with improvements in bleed rate and quality of life. The main toxicity seen within these studies has been early transient elevation in liver enzymes, with variable effect on transgene expression. Although long-term data are awaited, durable expression has been seen within the hemophilia dog model with no late-toxicity or oncogenesis. There are a number of phase III studies currently recruiting; however, there may be some limitations in translating these data to clinical practice, due to inclusion/exclusion criteria. AAV-based gene therapy is one of a number of novel approaches for treatment of hemophilia with other gene therapy (in vivo and ex vivo) and non-replacement therapies progressing through clinical trials. Availability of these high-cost novel therapeutics will require evolution of both clinical and financial healthcare services to allow equitable personalization of care for persons with hemophilia.

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15

Chuah, Marinee K. L., Desire Collen, and Thierry VandenDriessche. "Gene therapy for hemophilia." Journal of Gene Medicine 3, no. 1 (January 2001): 3–20. http://dx.doi.org/10.1002/1521-2254(200101/02)3:1<3::aid-jgm167>3.0.co;2-h.

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16

Kavakli, Kaan, Ozgur Cogulu, Semih Aydogdu, Hayal Ozkilic, Burak Durmaz, Ozgur Kirbiyik, Ferda Ozkinay, et al. "Prospective Evaluation of Chromosomal Breakages in Hemophiliac Children after Radioisotope Synovectomy with Yttrium90 and Rhenium186." Blood 112, no. 11 (November 16, 2008): 1219. http://dx.doi.org/10.1182/blood.v112.11.1219.1219.

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Abstract Radioisotope Synovectomy (RS) is defined as the intra-articular injection of radioisotopic agents with the aim of fibrosis on hypertrophic synovium in the target joint for hemophilia. Yttrium90 (Y90) and Rhenium186 (Re186) are approved isotopes in Europe. The only radioisotope which approved in the USA for RS is Phosphorus 32 (P32). We have successfully used Y90 and Re186 for 8 years in target joints of hemophiliac patients. For the last 30 years, no malignant transformation has been reported in hemophilia with RS. However, recently, development of acute lymphoblastic leukemia in two hemophiliac children after RS has been reported in the USA. Even though P32 was the responsible radioisotopic agent, safety concerns have arisen due to exposure to all type of radioisotopic agents which may cause chromosomal breakages (CBs) and oncological transformation. The aim of this prospective and Ethics commitee-approved study was to investigate the early genotoxic effect on peripheral blood lymphocytes induced by Y90 and Re186 in children who underwent RS for chronical synovitis. All patients and parents were informed according to Helsinki Decleration. Thirty-three patients with persistent synovitis (23 hemophilia-A, 9 hemophilia-B,1 FVII deficiency) were enrolled to the study. All patients were male except one case. The mean age was 16.4 ±6.2 years (range:8–40). RS was performed as an outpatient procedure by using Y90 for knees (n=9)(5 mCi) and Re186 for elbows and ankles (n=14)(2 mCi)(CIS Bio International/Gif-sur-Yvett Cedex-France). In 6 patients, both agents were used simultaneously in one session. No radioisotope leakage away from the injection site was observed during and after procedure. Heparinised peripheral blood samples were obtained for lymphocyte cultures from all patients at three different time points (prior to RS, after 3 days and after 90 days). Diepoxybutane (DEB) test was used for the evaluation of chromosomal breakages in patients by culturing their blood along with blood from a sex-matched control with a working solution of 11 ug/ml. Five μl pure DEB was added to 5 ml of sterile dH2O. Afterwards, 10 μl of the first solution was added to 1 ml of sterile dH2O. This is the working solution at 11 ug/ml. A total of 50 metaphases from each culture were examined and scored according to the procedure. All cytogenetic analysis were performed in the Medical Genetics Laboratory of Ege University Hospital. Due to technical problems, parameters of 29 patients were evaluated. Chromosomal breakages (CB) were found in 20 patients prior to treatment. We have found CBs in 4 additional patients after 3 days of RS. However, all these CBs were disappeared 90 days after. CBs were found to be persisted in 17 patients. Mean frequency of CBs was (0.0707±0.0829/1000 cells) and was not significantly increased after 3 days (0.0828±0.0747) but significantly decreased at 90 days (0.0379±0.0456). The difference of the results of two radioisotopes were not significant. In conclusion, although RS with Y90 and Re186 does not seem to induce the genotoxic effects significantly on peripheral blood lymphocytes in hemophilic children, the significant decrease in the number of CBs between the 3rd and 90th days may be accepted as a warning for the requirement of risk/benefit ratios which should be taken into account for any individual patient. Therefore medical treatment in hemophilia for synovitis should be suggested before RS and families should be informed properly.

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17

Lawn, R. M., W. I. Wood, J. Gitschier, K. L. Wion, D. Eaton, G. A. Vehar, and E. G. D. Tuddenham. "Cloned Factor VIII and the Molecular Genetics of Hemophilia." Cold Spring Harbor Symposia on Quantitative Biology 51 (January 1, 1986): 365–69. http://dx.doi.org/10.1101/sqb.1986.051.01.044.

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18

Peyvandi, Flora, Tom Kunicki, and David Lillicrap. "Genetic sequence analysis of inherited bleeding diseases." Blood 122, no. 20 (November 14, 2013): 3423–31. http://dx.doi.org/10.1182/blood-2013-05-505511.

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Abstract The genes encoding the coagulation factor proteins were among the first human genes to be characterized over 25 years ago. Since then, significant progress has been made in the translational application of this information for the 2 commonest severe inherited bleeding disorders, hemophilia A and B. For these X-linked disorders, genetic characterization of the disease-causing mutations is now incorporated into the standard of care and genetic information is used for risk stratification of treatment complications. With electronic databases detailing >2100 unique mutations for hemophilia A and >1100 mutations for hemophilia B, these diseases are among the most extensively characterized inherited diseases in humans. Experience with the genetics of the rare bleeding disorders is, as expected, less well advanced. However, here again, electronic mutation databases have been developed and provide excellent guidance for the application of genetic analysis as a confirmatory approach to diagnosis. Most recently, progress has also been made in identifying the mutant loci in a variety of inherited platelet disorders, and these findings are beginning to be applied to the genetic diagnosis of these conditions. Investigation of patients with bleeding phenotypes without a diagnosis, using genome-wide strategies, may identify novel genes not previously recognized as playing a role in hemostasis.

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19

High, Katherine. "AAV-mediated gene transfer for hemophilia." Genetics in Medicine 4 (December 2002): 56S—61S. http://dx.doi.org/10.1097/00125817-200211001-00012.

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20

Johnsen, Jill, Shelley N. Fletcher, Haley Huston, Sarah Roberge, Beth K. Martin, Martin Kircher, Neil C. Josephson, et al. "Novel Approach to and Results of Genetic Analysis of 3000 Hemophilia Patients Enrolled in the MyLifeOurFuture Initiative." Blood 128, no. 22 (December 2, 2016): 205. http://dx.doi.org/10.1182/blood.v128.22.205.205.

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Abstract Background Hemophilia A and B are rare X-linked bleeding disorders affecting ~1:5000 male births. Hemophilia genotype is important to inform reproductive planning, pregnancy, and neonatal management, risk of inhibitor formation and bleeding severity, and basic understanding of mechanisms of disease. In 2012, two separate surveys found only ~20% of patients with hemophilia had a genotype determined. MyLifeOurFuture (MLOF) was formed as a multi-sector collaboration between the American Thrombosis and Hemostasis Network (ATHN), the National Hemophilia Foundation (NHF), BloodworksNW (BWNW), and Biogen to provide hemophilia genotype analysis for patients in the U.S. and to create a Research Repository for future scientific discovery. Methods Participating hemophilia treatment centers (HTCs) contract through ATHN, enroll patients, obtain samples, and provide clinical results to patients. ATHN offers HTC provider education, a secure infrastructure for clinical data collection, and access for research proposals. NHF educates the bleeding disorders community about the initiative and supports recruitment. Biogen provides scientific collaboration and financial support. BWNW serves as the central sample processing and genotyping laboratory and houses the research sample repository. Genotyping was performed custom molecular inversion probes (MIPs) targeting the F8 and F9 genes and F8 inversions for simultaneous next generation sequencing (NGS) followed by confirmation of variants using standard genotyping methods.. Clinical results were returned to providers, and new variants were submitted to public databases. Results 69 HTCs enrolled the first 3000 patients in under 3 years. Clinically reportable DNA variants were detected in 98.1% (2357/2401) of hemophilia A and 99.3% (595/599) of hemophilia B patients. 924 unique variants were found; 285 were novel. Predicted gene disrupting variants were common in severe disease, while missense variants predominated in mild-moderate disease. The custom MIP-based NGS inversion screening method successfully detected F8 gene proximal and distal intron 22 inversion and intron 1 inversion variants. Unexpectedly, the NGS approach detected more than one reportable variants in 40 patients (10 females), a finding with potential clinical implications. NGS also detected 108 unique incidental variants unlikely to cause disease; 11 variants were previously reported associated with hemophilia. Interrogation of the ExAC database, which has data from >66,000 individuals without hemophilia, reports DNA variants distributed across the coding regions of both genes. Conclusions MLOF is the largest hemophilia genetics project performed to date, with plans to genotype over 6000 U.S. hemophilia patients. In the first 3000 patients, clinically reportable DNA variants were identifiedin nearly all patients. Our hemophilia NGS approach accurately identified F8 and F9 gene variants and is, to our knowledge, the first NGS method which can detect F8 inversions. The incidence of discovery of novel variation was high (30%) and novel variants were discovered continuously (per patient) over the course of the study, indicating that additional genetic variation in hemophilia likely remains undiscovered. Although both the F8 and F9 genes are thought to be conserved, we identified incidental variation in both genes, supporting caution in the interpretation of new variants. In summary, MLOF is a successful nationwide collaboration to genotype two rare bleeding disorders at scale which has contributed significantly towards DNA variant identification in the F8 and F9 genes in hemophilia. Through a consented research repository, MLOF data and samples, including phenotypic data from the ATHNdataset, will be accessible to providers and research communities for advancing our understanding of hemophilia and other disorders. Disclosures Johnsen: Octapharma: Consultancy; CSL Behring: Consultancy. Meltzer:Biogen: Employment.

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21

Kirchweger, Gina. "The National Hemophilia Foundation's Sixth Annual Workshop on Gene Therapies for Hemophilia." Molecular Therapy 8, no. 1 (July 2003): 11–12. http://dx.doi.org/10.1016/s1525-0016(03)00191-6.

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22

Astermark, Jan, Sharyne M. Donfield, Edward D. Gomperts, John Schwarz, Erika D. Menius, Anna Pavlova, Johannes Oldenburg, et al. "The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort." Blood 121, no. 8 (February 21, 2013): 1446–54. http://dx.doi.org/10.1182/blood-2012-06-434803.

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Key Points The data demonstrate the complexity of the genetic contribution to inhibitor development in people with hemophilia A. Potentially decisive markers have been identified, indicating the importance of further evaluation of intracellular signaling pathways.

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23

Hedner, Ulla, David Ginsburg, Jeanne M. Lusher, and Katherine A. High. "Congenital Hemorrhagic Disorders: New Insights into the Pathophysiology and Treatment of Hemophilia." Hematology 2000, no. 1 (January 1, 2000): 241–65. http://dx.doi.org/10.1182/asheducation.v2000.1.241.20000241.

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The diagnostic and treatment strategies related to hemophilia are rapidly evolving. This article focuses on some of the issues of importance. Diagnostic advances in molecular genetics are reviewed by Dr. Ginsburg in Section I, including the current state of knowledge regarding the mutations responsible for hemophilia, with reference to the potential clinical applications of DNA diagnosis and prenatal testing. Within the area of new therapeutic approaches in hemophilia, recombinant factor VIII and factor IX concentrates, their use and availability are addressed by Dr. Lusher in Section II as well as the use of so-called “primary prophylaxis” with the aim of decreasing long-term hemophilia athropathy. The use of radionuclide synovectomy as replacement for more invasive methods is also reviewed. Various approaches to the ongoing challenge of the management of hemophilia patients with inhibitors against factor VIII and factor IX are reviewed by Dr. Hedner in Section III, including the principles for immune tolerance induction and the use of recombinant factor VIIa to induce hemostasis in bleeding patients with inhibitors. In Section IV, gene therapy in hemophilia is reviewed by Dr. High, who focuses on recent developments in the rapidly moving field of gene therapy for hemophilia. Three phase I trials of gene therapy for hemophilia were initiated in 1999, and additional proposed trials are currently in the regulatory review process. Certain aspects of the pathophysiology of hemophilia make it an attractive model for a gene-based approach to treatment. These include latitude in choice of target tissue, a wide therapeutic window, the availability of small and large animal models of the disease, and the ease of determining therapeutic efficacy. Since there is very little published information regarding the ongoing trials, this section reviews the approaches being used, the published pre-clinical data, and considerations affecting clinical trial design in hemophilia gene therapy.

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Hedner, Ulla, David Ginsburg, Jeanne M. Lusher, and Katherine A. High. "Congenital Hemorrhagic Disorders: New Insights into the Pathophysiology and Treatment of Hemophilia." Hematology 2000, no. 1 (January 1, 2000): 241–65. http://dx.doi.org/10.1182/asheducation.v2000.1.241.241.

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Abstract The diagnostic and treatment strategies related to hemophilia are rapidly evolving. This article focuses on some of the issues of importance. Diagnostic advances in molecular genetics are reviewed by Dr. Ginsburg in Section I, including the current state of knowledge regarding the mutations responsible for hemophilia, with reference to the potential clinical applications of DNA diagnosis and prenatal testing. Within the area of new therapeutic approaches in hemophilia, recombinant factor VIII and factor IX concentrates, their use and availability are addressed by Dr. Lusher in Section II as well as the use of so-called “primary prophylaxis” with the aim of decreasing long-term hemophilia athropathy. The use of radionuclide synovectomy as replacement for more invasive methods is also reviewed. Various approaches to the ongoing challenge of the management of hemophilia patients with inhibitors against factor VIII and factor IX are reviewed by Dr. Hedner in Section III, including the principles for immune tolerance induction and the use of recombinant factor VIIa to induce hemostasis in bleeding patients with inhibitors. In Section IV, gene therapy in hemophilia is reviewed by Dr. High, who focuses on recent developments in the rapidly moving field of gene therapy for hemophilia. Three phase I trials of gene therapy for hemophilia were initiated in 1999, and additional proposed trials are currently in the regulatory review process. Certain aspects of the pathophysiology of hemophilia make it an attractive model for a gene-based approach to treatment. These include latitude in choice of target tissue, a wide therapeutic window, the availability of small and large animal models of the disease, and the ease of determining therapeutic efficacy. Since there is very little published information regarding the ongoing trials, this section reviews the approaches being used, the published pre-clinical data, and considerations affecting clinical trial design in hemophilia gene therapy.

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Pshenichnikova, O. S., and V. L. Surin. "Genetic Risk Factors for Inhibitor Development in Hemophilia A." Russian Journal of Genetics 57, no. 8 (August 2021): 867–77. http://dx.doi.org/10.1134/s1022795421080111.

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Antonarakis, Stylianos E. "Molecular Genetics of Coagulation Factor VIII Gene and Hemophilia A." Thrombosis and Haemostasis 74, no. 01 (1995): 322–28. http://dx.doi.org/10.1055/s-0038-1642697.

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Jayandharan, Giridhara, Arun Srivastava, and Alok Srivastava. "Role of Molecular Genetics in Hemophilia: From Diagnosis to Therapy." Seminars in Thrombosis and Hemostasis 38, no. 01 (February 2012): 64–78. http://dx.doi.org/10.1055/s-0031-1300953.

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Sukarova Stefanovska, E., P. Tchakarova, G. Petkov, and G. Efremov. "Molecular Characterization of Hemophilia a in Southeast Bulgaria." Balkan Journal of Medical Genetics 11, no. 1 (January 1, 2008): 55–60. http://dx.doi.org/10.2478/v10034-008-0018-9.

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Molecular Characterization of Hemophilia a in Southeast BulgariaThe results of molecular characterization of Hemophilia A in 50 patients from Southeast Bulgaria are presented. Southern blot analysis for the detection of inversions in intron 22, and polymerase chain reaction (PCR) followed by single strand conformation polymorphism (SSCP) or de-naturing gradient gel electrophoresis (DGGE) for screening of the coding sequences of the Factor VIII (FVIII) gene were used. A molecular defect was found in 35 (70%), the most frequent being an inversion in intron 22, found in 19 (38%) patients; an intron 1 inversion was not detected. In one severely affected patient, an Alu insert was found, which disrupted exon 14 at codon 1224. Nucleotide substitutions were found in 15 (30%) patients, the most frequent being an Arg531→Cys missense mutation in exon 11. The same nonsense mutation (codon -5,CGA>TGA) was found in two patients with a severe phenotype. Seven missense mutations (Asn90→Thr, Arg 372→His, Glu456→Val, Tyr473→His, Arg1689→ Cys, Arg2159→Cys and Arg2163→His) were detected in isolated families. Two of these (Asn90→Thr and Glu456→ Val) are being reported for the first time.

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Ça??layan, S. Hande, Yeşim Gökmen, Gülten Aktu??lu, Aytemiz Gürgey, and Steve S. Sommer. "Mutations associated with hemophilia B in Turkish patients." Human Mutation 10, no. 1 (1997): 76–79. http://dx.doi.org/10.1002/(sici)1098-1004(1997)10:1<76::aid-humu11>3.0.co;2-x.

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Lee, Mi Kyung, Minwoo Hwang, Hyunjoo Oh, and Kyoung Soo Kim. "Analysis of Sasang Constitutional Medicine as an Optimal Preventive Care Strategy for Hemophilia Patients." BioMed Research International 2020 (February 3, 2020): 1–5. http://dx.doi.org/10.1155/2020/4147803.

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Introduction. Medical improvements have allowed hemophilia patients to anticipate an increased quality of life and life expectancy similar to that of the general population. Analysis of the potential disease symptoms of hemophilia patients based on a survey of Sasang Constitutional Medicine (SCM) is important for optimal preventive care and adjunctive therapy to avoid life-threating complications. Aim. To predict potential disease symptoms from the viewpoint of SCM as a preventive care strategy for hemophilia patients. Methods. Sixty-one hemophilia patients responded to a survey on Sasang constitutional classification, hemophilia disease pattern, and original symptoms. Results. In terms of SCM type, the 61 of hemophilia patients included 37 Tae-Eum (60.7%), 18 So-Yang (29.5%), and 6 So-Eum (12.5%). Hemophilia was found to be higher in Tae-Eum type and lower in So-Yang and So-Eum types, while considering the distributional rate of Korean Sasang types. Most of the patients with Tae-Eum type had Joyeol or Ganyeol. Furthermore, the incidences of diabetes and high blood pressure were greater in Tae-Eum type than in those of other types. Conclusion. In order to increase the quality of life and overall life expectancy, hemophilia patients with Tae-Eum type should be treated through management according to SCM along with medicine against hemophilia as long-term preventive care. Diabetes and high blood pressure should be regularly monitored in patients with Tae-Eum type.

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Lebo, Roger V., Marion A. Koerper, Jong Hwa Kim, Jane Chueh, and Mitchell S. Golbus. "Prenatal diagnosis of hemophilia involving grandpaternal mosaicism." American Journal of Medical Genetics 47, no. 3 (September 1, 1993): 401–4. http://dx.doi.org/10.1002/ajmg.1320470321.

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Alexandre, Claudio O. P., and Israel Roisenberg. "A Genetic and Demographic Study of Hemophilia A in Brazil." Human Heredity 35, no. 4 (1985): 250–54. http://dx.doi.org/10.1159/000153554.

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Surin, V. L., E. Yu Demidova, D. S. Selivanova, Yu A. Luchinina, V. V. Salomashkina, O. S. Pshenichnikova, and E. A. Likhacheva. "Mutational analysis of hemophilia B in Russia: Molecular-genetic study." Russian Journal of Genetics 52, no. 4 (April 2016): 409–15. http://dx.doi.org/10.1134/s1022795416040116.

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Leuer, Marco, Johannes Oldenburg, Jean-Maurice Lavergne, Michael Ludwig, Andreas Fregin, Anton Eigel, Rolf Ljung, Anne Goodeve, Ian Peake, and Klaus Olek. "Somatic Mosaicism in Hemophilia A: A Fairly Common Event." American Journal of Human Genetics 69, no. 1 (July 2001): 75–87. http://dx.doi.org/10.1086/321285.

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35

Antonarakis, Stylianos E., Haig H. Kazazian, and Edward G. D. Tuddenham. "Molecular etiology of factor VIII deficiency in hemophilia A." Human Mutation 5, no. 1 (1995): 1–22. http://dx.doi.org/10.1002/humu.1380050102.

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Srivastava, A., A. K. Brewer, E. P. Mauser-Bunschoten, N. S. Key, S. Kitchen, A. Llinas, C. A. Ludlam, et al. "Guidelines for the management of hemophilia." Haemophilia 19, no. 1 (July 6, 2012): e1-e47. http://dx.doi.org/10.1111/j.1365-2516.2012.02909.x.

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Nathwani, Amit C., Andrew M. Davidoff, and Edward G. D. Tuddenham. "Advances in Gene Therapy for Hemophilia." Human Gene Therapy 28, no. 11 (November 2017): 1004–12. http://dx.doi.org/10.1089/hum.2017.167.

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Philippidis, Alex. "FDA Prioritizes Biomarin's Hemophilia Gene Therapy." Human Gene Therapy 31, no. 5-6 (March 1, 2020): 283–85. http://dx.doi.org/10.1089/hum.2020.29114.bfs.

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39

Gouw, Samantha, and H. Marÿke van den Berg. "The Multifactorial Etiology of Inhibitor Development in Hemophilia: Genetics and Environment." Seminars in Thrombosis and Hemostasis 35, no. 08 (November 2009): 723–34. http://dx.doi.org/10.1055/s-0029-1245105.

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40

Lawn, Richard M. "The molecular genetics of hemophilia: Blood clotting factors VIII and IX." Cell 42, no. 2 (September 1985): 405–6. http://dx.doi.org/10.1016/0092-8674(85)90094-7.

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Sorenson, James R., Tracey Jennings-Grant, and Jamie Newman. "Communication about carrier testing within hemophilia A families." American Journal of Medical Genetics 119C, no. 1 (April 14, 2003): 3–10. http://dx.doi.org/10.1002/ajmg.c.10001.

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42

Driessche, Thierry, Desire Collen, and Marinee Chuah. "Viral Vector-Mediated Gene Therapy for Hemophilia." Current Gene Therapy 1, no. 3 (September 1, 2001): 301–15. http://dx.doi.org/10.2174/1566523013348508.

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43

Funnell, Alister P. W., and Merlin Crossley. "Hemophilia B Leyden and once mysterious cis-regulatory mutations." Trends in Genetics 30, no. 1 (January 2014): 18–23. http://dx.doi.org/10.1016/j.tig.2013.09.007.

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Derbent, Murat, Namık Özbek, Füsun Alehan, and Zerrin Yılmaz. "Chromosome 22q11.2 microdeletion in a patient with hemophilia A." Annales de Génétique 47, no. 2 (April 2004): 181–84. http://dx.doi.org/10.1016/j.anngen.2003.11.001.

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Beskorovainaya, T. S., T. B. Milovidova, O. A. Schagina, O. P. Ryzhkova, and A. V. Polyakov. "Complex Molecular Diagnostics of Hemophilia A in Russian Patients." Russian Journal of Genetics 55, no. 8 (August 2019): 1015–24. http://dx.doi.org/10.1134/s1022795419080027.

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46

Haris, I. I., P. M. Green, D. R. Bentley, and F. Giannelli. "Mutation detection by fluorescent chemical cleavage: application to hemophilia B." Genome Research 3, no. 5 (April 1, 1994): 268–71. http://dx.doi.org/10.1101/gr.3.5.268.

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47

Spiro, Roberta, and Marie-Louise Lubs. "Survey of amniocentesis for fetal sex determination in hemophilia carriers." Clinical Genetics 10, no. 5 (April 23, 2008): 337–42. http://dx.doi.org/10.1111/j.1399-0004.1976.tb00058.x.

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David, Dezso, Isabel Moreira, Sara Morais, and Graça De Deus. "Five novel factor IX mutations in unrelated hemophilia B patients." Human Mutation 11, S1 (1998): S301—S303. http://dx.doi.org/10.1002/humu.1380110194.

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49

Feng, Jinong, Qiang Liu, Joni Drost, and Steve S. Sommer. "Deep intronic mutations are rarely a cause of hemophilia B." Human Mutation 14, no. 3 (1999): 267–68. http://dx.doi.org/10.1002/(sici)1098-1004(1999)14:3<267::aid-humu11>3.0.co;2-i.

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50

Lundstrom, Kenneth. "RNA Viruses as Tools in Gene Therapy and Vaccine Development." Genes 10, no. 3 (March 1, 2019): 189. http://dx.doi.org/10.3390/genes10030189.

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RNA viruses have been subjected to substantial engineering efforts to support gene therapy applications and vaccine development. Typically, retroviruses, lentiviruses, alphaviruses, flaviviruses rhabdoviruses, measles viruses, Newcastle disease viruses, and picornaviruses have been employed as expression vectors for treatment of various diseases including different types of cancers, hemophilia, and infectious diseases. Moreover, vaccination with viral vectors has evaluated immunogenicity against infectious agents and protection against challenges with pathogenic organisms. Several preclinical studies in animal models have confirmed both immune responses and protection against lethal challenges. Similarly, administration of RNA viral vectors in animals implanted with tumor xenografts resulted in tumor regression and prolonged survival, and in some cases complete tumor clearance. Based on preclinical results, clinical trials have been conducted to establish the safety of RNA virus delivery. Moreover, stem cell-based lentiviral therapy provided life-long production of factor VIII potentially generating a cure for hemophilia A. Several clinical trials on cancer patients have generated anti-tumor activity, prolonged survival, and even progression-free survival.

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