To see the other types of publications on this topic, follow the link: Genetic/blood disorders.
Journal articles on the topic 'Genetic/blood disorders'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Genetic/blood disorders.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Kurtzberg, J. "Cord blood transplantation in genetic disorders." Biology of Blood and Marrow Transplantation 10, no. 10 (October 2004): 735–36. http://dx.doi.org/10.1016/j.bbmt.2004.06.021.
Full text
2
Owayes Muaffaq Hamed, Amjad Abdul-hadi Mohammed, and Raed Salem Alsaffar. "Genetic Metabolism Disorders in Newborn." International Journal for Research in Applied Sciences and Biotechnology 8, no. 1 (January 13, 2021): 77–81. http://dx.doi.org/10.31033/ijrasb.8.1.9.
Full textAbstract:
Babies with any type of metabolic disorders lack the ability to break down the food well, which may induce too little amino acids, phenylalanine and blood sugar to the body, there are numerous kinds of this disorders, most of babies with a genetic metabolic disease have many mutation in gene that coded an enzyme which results a deficiency in same enzyme are hundreds of these disorders and they were diagnosed by their symptoms and the treatment method. The treatment methods of the metabolic disorder depend on the specific type of disorders, inborn metabolic disease are some-time treated with dietary guidance, and other childcare choices, many hereditary metabolic disease are initially caused by gene mutations and that transferred from parents to offspring.
3
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.
Full textAbstract:
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.
4
Elbagoury, Marwan, Abdulelah Ismail Qadi, Ayman Hejazi, Fahad Alabbas, Ghaleb El Yamany, Hussain H. Al Saeed, and Ohoud F. Kashari. "Prevalence of Gaucher Disease in Patients of Unknown Cause of Splenomegaly and/or Thrombocytopenia in Saudi Arabia." Blood 136, Supplement 1 (November 5, 2020): 32–33. http://dx.doi.org/10.1182/blood-2020-140563.
Full textAbstract:
Rationale: Gaucher disease (GD) is the most common amongst the lysosomal storage disorders. Prevalence of GD in Saudi Arabia is not available in published literature and it is expected to be high and remains undiagnosed. In 2004, a Saudi study reported that GD accounts for 6% of all genetic metabolic disorders. While acid sphingomyelinase deficiency (ASMD) is a rare progressive genetic disorder with no clear data about its incidence in Saudi Arabia. Consequently, this study proposes to determine the prevalence of GD and ASMD in outpatient settings in Saudi Arabia by screening patients with unknown causes of splenomegaly and/or thrombocytopenia. These data will change the local practice and increase the awareness towards GD and ASMD in Saudi Arabia. Objectives: To determine the prevalence of GD in high risk group (defined as patients with splenomegaly and/or thrombocytopenia of unknown cause) and describe their characteristics. We also aim to determine the prevalence of ASMD in high risk group. Methods: A multi-center, observational, study will be conducted in 25 specialty care centres across Saudi Arabia, these centres are mainly focusing on pediatric hematology, adult hematology and hemato-pathology. Female or male patients (aged 2-75 years) will deemed eligible if they have clinical, instrumental or laboratory signs of splenomegaly or thrombocytopenia over a period of 12 months without definitive cause. These patients will be tested for acid β-glucosidase and acid sphingomyelinase enzymes activity on dried blood spot (DBS) samples. Patients with hematological malignancies, hemolytic anemia, and/or thalassemia (except sickle cell disease) will be excluded. A total of 400 patients from Saudi Arabia who fulfill the eligibility criteria will be enrolled in the study. All patient data will be collected in a single visit. Each enrolled patient will visit the investigator for a baseline visit. The investigator will contact them later for sharing the investigation blood test results. During the baseline visit, data and blood sample for enzyme tests and genotyping will be collected by the investigator/designated person at the site. Discussion: Arab world represents one of the leading regions in terms of the incidence of congenital and genetic disorders; a growing body of published literature reported a notable trends towards higher incidence of congenital and genetic diseases, compared to other parts of the world(1). High consanguinity rates which reach up to 60% in some regions, high prevalence of haemoglobinopathies and metabolic disorders, relatively high maternal and parental age, and lack of proper genetic screening were reported as contributing factors for this high prevalence of genetic disorders in the Arab world(1-3). In Saudi Arabia, the situation appears to be no different as previous retrospective studies showed a relatively high incidence of genetic diseases such as inborn error of metabolism. The data of the present study will change the local practice and increase the awareness towards GD and ASMD in Saudi Arabia. References: Al-Gazali L, Hamamy H, Al-Arrayad S. Genetic disorders in the Arab world. BMJ [Internet]. 2006 Oct 21 [cited 2019 Jun 29];333(7573):831-4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17053236 Al-Gazali LI, Alwash R, Abdulrazzaq YM. United Arab Emirates: Communities and Community Genetics. Public Health Genomics [Internet]. 2005 [cited 2019 Jun 29];8(3):186-96. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16113536 Wahab AA, Bener A, Teebi AS. The incidence patterns of Down syndrome in Qatar. Clin Genet [Internet]. 2006 Mar 30 [cited 2019 Jun 29];69(4):360-2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16630172 Disclosures No relevant conflicts of interest to declare.
5
Canver, Matthew C., and Stuart H. Orkin. "Customizing the genome as therapy for the β-hemoglobinopathies." Blood 127, no. 21 (May 26, 2016): 2536–45. http://dx.doi.org/10.1182/blood-2016-01-678128.
Full textAbstract:
Abstract Despite nearly complete understanding of the genetics of the β-hemoglobinopathies for several decades, definitive treatment options have lagged behind. Recent developments in technologies for facile manipulation of the genome (zinc finger nucleases, transcription activator-like effector nucleases, or clustered regularly interspaced short palindromic repeats–based nucleases) raise prospects for their clinical application. The use of genome-editing technologies in autologous CD34+ hematopoietic stem and progenitor cells represents a promising therapeutic avenue for the β-globin disorders. Genetic correction strategies relying on the homology-directed repair pathway may repair genetic defects, whereas genetic disruption strategies relying on the nonhomologous end joining pathway may induce compensatory fetal hemoglobin expression. Harnessing the power of genome editing may usher in a second-generation form of gene therapy for the β-globin disorders.
6
Tanaka, Tiffany N., and Rafael Bejar. "MDS overlap disorders and diagnostic boundaries." Blood 133, no. 10 (March 7, 2019): 1086–95. http://dx.doi.org/10.1182/blood-2018-10-844670.
Full textAbstract:
Abstract Myelodysplastic syndromes (MDS) are clonal diseases defined by clinical, morphologic, and genetic features often shared by related myeloid disorders. The diagnostic boundaries between these diseases can be arbitrary and not necessarily reflective of underlying disease biology or outcomes. In practice, measures that distinguish MDS from related disorders may be difficult to quantify and can vary as disease progression occurs. Patients may harbor findings that are not consistent with a single diagnostic category. Several overlap disorders have been formally described, such as the myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). These disorders are characterized by hematopoietic dysplasia with increased proliferation of monocytes, neutrophils, or platelets. They may have mutational profiles that distinguish them from the disorders they resemble and reflect important differences in pathophysiology. MDS also shares diagnostic borders with other diseases. For example, aplastic anemia and hypoplastic MDS can be difficult to distinguish in patients with pancytopenia and bone marrow hypocellularity. Genetic features may help in this regard, because they can identify differences in prognosis and risk of progression. The boundary between MDS and secondary acute myeloid leukemia (sAML) is arbitrarily defined and has been redefined over the years. Genetic studies have demonstrated that sAML clones can precede clinical progression from MDS by many months, suggesting that MDS with excess blasts could be viewed as an overlap between a dysplastic bone marrow failure syndrome and an oligoblastic leukemia. This review will describe the diagnostic boundaries between MDS, MDS/MPNs, sAML, clonal hematopoiesis of indeterminate potential, clonal cytopenia of undetermined significance, and aplastic anemia and how genetic approaches may help to better define them.
7
Marks, I. M. "Genetics of Fear and Anxiety Disorders." British Journal of Psychiatry 149, no. 4 (October 1986): 406–18. http://dx.doi.org/10.1192/bjp.149.4.406.
Full textAbstract:
From protozoa to mammals, organisms have been selectively bred for genetic differences in defensive behaviour which are accompanied by differences in brain and other biological functions. Studies of twins indicate some genetic control of normal human fear from infancy onwards, of anxiety as a symptom and as a syndrome, and of phobic and obsessive- compulsive phenomena. Anxiety disorders are more common among the relatives of affected probands than of controls, especially among female and first-degree relatives; alcoholism and secondary depression may also be over-represented. Familial influences have been found for panic disorder, agoraphobia, and obsessive-compulsive problems. Panic disorder in depressed probands increases the risk to their relatives of phobia as well as of panic disorder, major depression, and alcoholism. The strongest family history of all anxiety disorders is seen in blood-injury phobia; even though it can be successfully treated by exposure, its roots may lie in a genetically determined specific autonomic susceptibility. Some genetic effects can be modified by environmental means.
8
Dahlbäck, Björn. "Advances in understanding pathogenic mechanisms of thrombophilic disorders." Blood 112, no. 1 (July 1, 2008): 19–27. http://dx.doi.org/10.1182/blood-2008-01-077909.
Full textAbstract:
AbstractVenous thromboembolism is a major medical problem, annually affecting 1 in 1000 individuals. It is a typical multifactorial disease, involving both genetic and circumstantial risk factors that affect a delicate balance between procoagulant and anticoagulant forces. In the last 50 years, the molecular basis of blood coagulation and the anticoagulant systems that control it have been elucidated. This has laid the foundation for discoveries of both common and rare genetic traits that tip the natural balance in favor of coagulation, with a resulting lifelong increased risk of venous thrombosis. Multiple mutations in the genes for anticoagulant proteins such as antithrombin, protein C, and protein S have been identified and constitute important risk factors. Two single mutations in the genes for coagulation factor V (FV Leiden) and prothrombin (20210G>A), resulting from approximately 20 000-year-old mutations with subsequent founder effects, are common in the general population and constitute major genetic risk factors for thrombosis. In celebration of the 50-year anniversary of the American Society of Hematology, this invited review highlights discoveries that have contributed to our present understanding of the systems that control blood coagulation and the genetic factors that are involved in the pathogenesis of venous thrombosis.
9
Graham, Nicholas, Joey Ward, Breda Cullen, Keira Johnston, Rona Strawbridge, Amy Ferguson, Daniel Mackay, et al. "SA8INVESTIGATING SHARED GENETIC MECHANISMS BETWEEN MOOD DISORDERS AND BLOOD PRESSURE." European Neuropsychopharmacology 29 (2019): S1192. http://dx.doi.org/10.1016/j.euroneuro.2018.08.230.
Full text
10
Lutsenko, T. "Fetal microchimerism and prenatal diagnostic of genetic disorders." Cell and Organ Transplantology 4, no. 1 (May 31, 2016): 124–31. http://dx.doi.org/10.22494/cot.v4i1.2.
Full textAbstract:
It is often require an invasive diagnosis based on karyotyping of cells from amniotic fluid, chorionic villi and cord blood in case of the fetus pathologies during pregnancy. The performance of these procedures has a risk of pregnancy complications or procedure-induced miscarriage. Therefore the investigators have nowadays been developing several approaches which would be capable to replace invasive diagnosis by alternative and safe non-invasive methods for detection of possible pregnancy pathology. Fetal microchimerism phenomenon and reliable strategies of fetal cells enrichment during early embryogenesis are reviewed. Fetal cells circulating in the peripheral blood of pregnant women has been described as a potential source of fetus genetic material in non-invasive prenatal diagnosis for chromosomal aberrations.
11
Levine, Ross L., and D. Gary Gilliland. "Myeloproliferative disorders." Blood 112, no. 6 (September 15, 2008): 2190–98. http://dx.doi.org/10.1182/blood-2008-03-077966.
Full textAbstract:
Abstract In 1951 William Dameshek classified polycythemia vera (PV), essential thombocytosis (ET), and primary myelofibrosis (PMF) as pathogenetically related myeloproliferative disorders (MPD). Subsequent studies demonstrated that PV, ET, and PMF are clonal disorders of multipotent hematopoietic progenitors. In 2005, a somatic activating mutation in the JAK2 nonreceptor tyrosine kinase (JAK2V617F) was identified in most patients with PV and in a significant proportion of patients with ET and PMF. Subsequent studies identified additional mutations in the JAK-STAT pathway in some patients with JAK2V617F− MPD, suggesting that constitutive activation of this signaling pathway is a unifying feature of these disorders. Although the discovery of mutations in the JAK-STAT pathway is important from a pathogenetic and diagnostic perspective, important questions remain regarding the role of this single disease allele in 3 related but clinically distinct disorders, and the role of additional genetic events in MPD disease pathogenesis. In addition, these observations provide a foundation for development of small molecule inhibitors of JAK2 that are currently being tested in clinical trials. This review will discuss our understanding of the pathogenesis of PV, ET, and PMF, the potential role of JAK2-targeted therapy, and the important unanswered questions that need to be addressed to improve clinical outcome.
12
Pardanani, Animesh, Brooke L. Fridley, Terra L. Lasho, D. Gary Gilliland, and Ayalew Tefferi. "Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders." Blood 111, no. 5 (March 1, 2008): 2785–89. http://dx.doi.org/10.1182/blood-2007-06-095703.
Full textAbstract:
JAK2V617F is an acquired mutation associated with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We tested the hypothesis that the paradox of a single disease allele associated with 3 distinctive clinical phenotypes could be explained in part by host-modifying influences. We screened for genetic variation within 4 candidate genes involved in JAK-STAT signaling, including receptors for erythropoietin (EPOR), thrombopoietin (MPL), and granulocyte colony-stimulating factor (GCSFR), and JAK2. We genotyped 32 linkage disequilibrium tag single nucleotide polymorphism (SNP) loci in 179 white patients: 84 had PV, 58 had PMF, and 37 had ET. Genotype-phenotype analysis showed 3 JAK2 SNPs (rs7046736, rs10815148, and rs12342421) to be significantly but reciprocally associated with PV (P < .001 for all; odds ratio = 0.16, 2.72, and 2.46, respectively) and ET (P < .001 for all; odds ratio = 3.05, 0.29, and 0.30, respectively) but not with PMF. Three additional JAK2 SNPs (rs10758669, rs3808850, and rs10974947) and a single EPOR SNP (rs318699) were also significantly associated with PV but not with ET or PMF. Finally, intragene haplotypes in JAK2 were significantly associated with PV only. Thus, host genetic variation may contribute to phenotypic diversity among myeloproliferative disorders, including in the presence of a shared disease allele.
13
Downes, Kate, Karyn Megy, Daniel Duarte, Minka Vries, Johanna Gebhart, Stefanie Hofer, Olga Shamardina, et al. "Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders." Blood 134, no. 23 (December 5, 2019): 2082–91. http://dx.doi.org/10.1182/blood.2018891192.
Full text
14
Kennedy, Alyssa L., and Akiko Shimamura. "Genetic predisposition to MDS: clinical features and clonal evolution." Blood 133, no. 10 (March 7, 2019): 1071–85. http://dx.doi.org/10.1182/blood-2018-10-844662.
Full textAbstract:
Abstract Myelodysplastic syndrome (MDS) typically presents in older adults with the acquisition of age-related somatic mutations, whereas MDS presenting in children and younger adults is more frequently associated with germline genetic predisposition. Germline predisposition is increasingly recognized in MDS presenting at older ages as well. Although each individual genetic disorder is rare, as a group, the genetic MDS disorders account for a significant subset of MDS in children and young adults. Because many patients lack overt syndromic features, genetic testing plays an important role in the diagnostic evaluation. This review provides an overview of syndromes associated with genetic predisposition to MDS, discusses implications for clinical evaluation and management, and explores scientific insights gleaned from the study of MDS predisposition syndromes. The effects of germline genetic context on the selective pressures driving somatic clonal evolution are explored. Elucidation of the molecular and genetic pathways driving clonal evolution may inform surveillance and risk stratification, and may lead to the development of novel therapeutic strategies.
15
Al Arrayed, S. S. "Review of the spectrum of genetic diseases in Bahrain." Eastern Mediterranean Health Journal 5, no. 6 (December 15, 1999): 1114–20. http://dx.doi.org/10.26719/1999.5.6.1114.
Full textAbstract:
This paper looks at some of the studies on genetic disorders conducted in Bahrain. The disorders covered include: genetic blood disorders, metabolic disorders, chromosomal disorders, including Down syndrome, and cystic fibrosis. The rate of consanguinity in Bahrain and the results of premarital counselling are also discussed
16
Haghshenas, Sadegheh, Michael A. Levy, Jennifer Kerkhof, Erfan Aref-Eshghi, Haley McConkey, Tugce Balci, Victoria Mok Siu, et al. "Detection of a DNA Methylation Signature for the Intellectual Developmental Disorder, X-Linked, Syndromic, Armfield Type." International Journal of Molecular Sciences 22, no. 3 (January 23, 2021): 1111. http://dx.doi.org/10.3390/ijms22031111.
Full textAbstract:
A growing number of genetic neurodevelopmental disorders are known to be associated with unique genomic DNA methylation patterns, called episignatures, which are detectable in peripheral blood. The intellectual developmental disorder, X-linked, syndromic, Armfield type (MRXSA) is caused by missense variants in FAM50A. Functional studies revealed the pathogenesis to be a spliceosomopathy that is characterized by atypical mRNA processing during development. In this study, we assessed the peripheral blood specimens in a cohort of individuals with MRXSA and detected a unique and highly specific DNA methylation episignature associated with this disorder. We used this episignature to construct a support vector machine model capable of sensitive and specific identification of individuals with pathogenic variants in FAM50A. This study contributes to the expanding number of genetic neurodevelopmental disorders with defined DNA methylation episignatures, provides an additional understanding of the associated molecular mechanisms, and further enhances our ability to diagnose patients with rare disorders.
17
Eckstein, Olive S., Nitya Gulati, Lisa Forbes, Erin Peckham-Gregory, Nmazuo Wudo Ozuah, M. Cecilia Poli, Tiphanie Vogel, et al. "Genomic Characterization of a Pediatric Cohort with Non-Malignant Lymphoproliferative Disorders." Blood 134, Supplement_1 (November 13, 2019): 83. http://dx.doi.org/10.1182/blood-2019-131884.
Full textAbstract:
Introduction: Pediatric non-malignant lymphoproliferative disorders (LPDs) are a clinically and genetically heterogeneous. While transient lymphadenopathy is extremely common and rarely dangerous, long-standing immune dysregulation and lymphoproliferation in children may be life-threatening. Data to guide evaluation and treatment of children with benign LPD are lacking. The primary objective of this study was to define the genomic spectrum and clinical characteristics of a cohort of children with nonmalignant LPD. Identification of the underlying pathogenic mechanisms may facilitate timely interventions and potentially guide optimal therapeutic strategies. Method s: Patients at Texas Children's Hospital and collaborating referral centers who met criteria for non-malignant LPD were offered participation in this study, approved by the Baylor College of Medicine Institutional Review Board. LPD was defined as persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant EBV infection. Chronic or significant EBV infection was defined as recurrent or persistent EBV viremia more than 3 months, invasive EBV disease, or EBV PCR copies >100,000. All subjects and/or family members provided written informed consent to have their clinical and genetic information published. Genetic testing was performed clinically or through research-based whole-exome sequencing (WES). Results : Fifty-one subjects from 47 different families with non-malignant LPD were identified. Median age at disease presentation was 3.3 years (range 3.9 weeks - 21 years) with nearly equal proportions of males (n = 26) and females (n = 25). Almost half of subjects were Hispanic (49%), and 29% were non-Hispanic white. Fifteen subjects (29%) met HLH-2004 diagnostic criteria for HLH. Twenty-one patients had EBV-associated lymphoproliferative disorders (EBV-LPD) and 6 of the 51 ultimately developed malignancy. Clinical genetic testing was performed in 29 patients, and research-based WES was performed in 44 patients. Potential disease-causing genetic defects were identified in 62% of families. Of these pathogenic variants, targeted therapies may be effective for treatment in at least 10 of the conditions (17 subjects, 33%). Furthermore, genetic results supported potential for curative HSCT in 35% of the patients. Mechanistically, all of the LPD-associated genes could be placed into 1 of 3 categories: 1) defective control of lymphocyte activity; 2) impaired lymphocyte activation, cytoskeletal organization, and apoptosis; and 3) dysregulated inflammation. Ten-year survival for the entire cohort was 72.4% with a median 5.6 years of follow-up (range 0.10 - 26.6). Patients without evidence of a genetic explanation had a lower ten-year survival compared to those patients for whom a genetic explanation was identified (48% versus 82%, respectively, p=0.03). When both EBV-LPD and genetic explanation were considered, the ten-year survival estimate for those with EBV-associated disease and no genetic explanation was significantly worse than those with EBV-associated disease and a genetic explanation (17% vs. 90%; p =0.002). Patients without EBV-associated disease were at lower risk of death than those with EBV-LPD. Evaluating outcomes associated with maximum treatment received, ten-year survival was lowest (25% survival) among those who underwent HSCT. Conclusion s: Pediatric non-malignant LPD represents a group of conditions with high risk of death. WES identified actionable mutations in the majority of LPD cases in this cohort. Early identification of these mutations can guide therapy by confirming diagnosis, revealing molecular targets and/or supporting definitive therapy with stem cell transplant. Disclosures Forbes: Takeda: Consultancy. Jolles:CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; LFB: Consultancy, Honoraria, Research Funding, Speakers Bureau; UCB Pharma: Consultancy, Other: Drug Safety Committee; Shire/Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharming: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Heslop:Marker Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allovir: Equity Ownership; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cell Medica: Research Funding. Rouce:Novartis: Consultancy, Honoraria; Tessa Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria.
18
Baz, Betoul, Tarek Owaidah, Majed Dasouki, Mohammed Abouelhoda, Dorota Monies, and Nada Al Tassan. "Informing Clinical Decision and Policy Making in Blood Related Disorders Using Targeted Next Generation Sequencing." Blood 134, Supplement_1 (November 13, 2019): 5776. http://dx.doi.org/10.1182/blood-2019-122370.
Full textAbstract:
Decision making in the public healthcare system is heavily invested in screening and preventative medicine in addition to the translation of national initiatives that help in implementing precision medicine. Molecular testing for cancers and inherited disorders helps families, patients and healthcare providers in disease management. Different genome programs and genetics initiatives around the world are contributing and providing data to help decision makers, pharmaceutical companies and other health related commercial entities to tailor diagnosis and treatment in a healthcare era that honors molecular individuality and population differences. The Saudi Human Genome Program (SHGP) is a national program committed to sequencing 100,000 genomes. In its early stages, it focused on understanding monogenic disorders. The data output was then expanded to allow researchers to interrogate the genetics of complex disorders and understand the molecular landscape of this highly inbred population. The results of the first phase of this program (consisting 35000 WES and gene panels and 2000 WGS) was translated into the establishment of a knowledge database of population specific mutations and single nucleotide variants (SNVs) that is used for molecular diagnosis. This was translated to a definitive molecular diagnosis in nearly half of ~2500 cases with Mendelian monogenic disorders using 13 targeted gene panels. To date; the SHGP knowledge database contains more than 2000 disease causing mutations and more that 4 million SNVs. In the Kingdom, there are two established national screening programs, premarital and newborn. These programs are extremely powerful at serving patients and carriers/family members equally, and will further benefit from the availability of population specific molecular databases. As we soar towards the mid-phase of the program, it has become obviously a valuable platform to inform clinical decision and policy making. The presumed presentation of carriers and family members in light of autosomal recessive inheritance is indicative of possible missed diagnosis when they are asymptomatic or present with milder clinical features, creating heavier burdens on the healthcare system. As further evidence emerges, genomics will continue to change practice in other healthcare areas including cancer and chronic diseases. In this study, we present rare genetic variants in common and rare bleeding disorders, where we have looked at data from the SHGP with both disease stratification and blindly to redefine and classify the rarity of pathogenic genetic variants in associated genes. We assessed an initial set of 1400 individuals using a targeted gene panel consisting of 393 genes implicated in nonmalignant blood related disorders (SHGP heme panel). We looked for variants and mutations to reclassify bleeding disorders based on the incidence of carriers and affected individuals. We then used a replication set of ~5000 WES to validate pathogenicity and assess allele frequencies. Our data will help impact decision making for effective screening and prevention of common blood related disorders and will aid in increasing the diagnostic yield, identifying predisposition markers and implementing better genetic counseling programs. Table Disclosures No relevant conflicts of interest to declare.
19
Mannucci, Pier Mannuccio, Stefano Duga, and Flora Peyvandi. "Recessively inherited coagulation disorders." Blood 104, no. 5 (September 1, 2004): 1243–52. http://dx.doi.org/10.1182/blood-2004-02-0595.
Full textAbstract:
Abstract Deficiencies of coagulation factors other than factor VIII and factor IX that cause bleeding disorders are inherited as autosomal recessive traits and are rare, with prevalences in the general population varying between 1 in 500 000 and 1 in 2 million for the homozygous forms. As a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects, and the actual management of bleeding episodes are not as well established as for hemophilia A and B. We investigated more than 1000 patients with recessively inherited coagulation disorders from Italy and Iran, a country with a high rate of recessive diseases due to the custom of consanguineous marriages. Based upon this experience, this article reviews the genetic basis, prevalent clinical manifestations, and management of these disorders. The steps and actions necessary to improve the condition of these often neglected patients are outlined.
20
Camaschella, Clara. "Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders." Blood 106, no. 12 (December 1, 2005): 3710–17. http://dx.doi.org/10.1182/blood-2005-05-1857.
Full textAbstract:
Genetic analysis of hemochromatosis has led to the discovery of a number of genes whose mutations disrupt iron homeostasis and lead to iron overload. The introduction of molecular tests into clinical practice has provided a tool for early diagnosis of these conditions. It has become clear that hemochromatosis includes a spectrum of disorders that range from simple biochemical abnormalities to chronic asymptomatic tissue damage in midlife to serious life-threatening diseases in young subjects. Molecular studies have identified the systemic loop that controls iron homeostasis and is centered on the hepcidin-ferroportin interaction. The complexity of this regulatory pathway accounts for the genetic heterogeneity of hemochromatosis and related disorders and raises the possibility that genes encoding components of the pathway may be modifiers of the main genotype. Molecular diagnosis has improved the classification of the genetic conditions leading to iron overload and identified novel entities, characterized by both iron loading and variable degrees of anemia. Despite the progress in the diagnosis, classification, and mechanisms of iron overload disorders, the treatment of affected patients continues to rely on regular phlebotomy. Understanding the molecular circuitry of iron control may lead to the identification of potential therapeutic targets for novel treatment strategies to be used in association with or as an alternative to phlebotomy.
21
Canna, Scott W., and Rebecca A. Marsh. "Pediatric hemophagocytic lymphohistiocytosis." Blood 135, no. 16 (April 16, 2020): 1332–43. http://dx.doi.org/10.1182/blood.2019000936.
Full textAbstract:
Abstract Hemophagocytic lymphohistiocytosis (HLH) is a syndrome describing patients with severe systemic hyperinflammation. Characteristic features include unremitting fever, cytopenias, hepatosplenomegaly, and elevation of typical HLH biomarkers. Patients can develop hepatitis, coagulopathy, liver failure, central nervous system involvement, multiorgan failure, and other manifestations. The syndrome has a high mortality rate. More and more, it is recognized that while HLH can be appropriately used as a broad summary diagnosis, many pediatric patients actually suffer from an expanding spectrum of genetic diseases that can be complicated by the syndrome of HLH. Classic genetic diseases in which HLH is a typical and common manifestation include pathogenic changes in familial HLH genes (PRF1, UNC13D, STXBP2, and STX11), several granule/pigment abnormality genes (RAB27A, LYST, and AP3B1), X-linked lymphoproliferative disease genes (SH2D1A and XIAP), and others such as NLRC4, CDC42, and the Epstein-Barr virus susceptibility diseases. There are many other genetic diseases in which HLH is an infrequent complication of the disorder as opposed to a prominent manifestation of the disease caused directly by the genetic defect, including other primary immune deficiencies and inborn errors of metabolism. HLH can also occur in patients with underlying rheumatologic or autoinflammatory disorders and is usually designated macrophage activation syndrome in those settings. Additionally, HLH can develop in patients during infections or malignancies without a known (or as-yet-identified) genetic predisposition. This article will attempt to summarize current concepts in the pediatric HLH field as well as offer a practical diagnostic and treatment overview.
22
Soulier, Jean. "Introduction to a review series on secondary leukemia." Blood 136, no. 1 (July 2, 2020): 1. http://dx.doi.org/10.1182/blood.2019004171.
Full textAbstract:
In this commissioned series of reviews introduced by Associate Editor Jean Soulier, experts provide new insights into the pathobiology of secondary acute myeloid leukemias arising in diverse genetic or acquired, benign or malignant hematologic disorders.
23
Li, Ka, and Rafat Ahmed. "Providing Primary Care to Children Diagnosed with Myosin Heavy Chain 9-Related Platelet Disorder: A Case Report and Review of Literature." Blood 132, Supplement 1 (November 29, 2018): 5828. http://dx.doi.org/10.1182/blood-2018-99-113967.
Full textAbstract:
Abstract Introduction: Myosin-heavy chain 9 (MYH9)-related platelet disorders are a group of rare inherited thrombocytopenias, encompassing four syndromes, such as May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome and Sebastian platelet syndrome. Typically diagnosed in adulthood, this disorder presents with chronic thrombocytopenia in all affected individuals with varying bleeding tendencies. Other clinical manifestations may include nephritis leading to end-stage renal disease, sensorineural hearing impairment and presenile cataracts. It is often misdiagnosed as autoimmune thrombocytopenia, which can lead to inappropriate treatment with corticosteroids or intravenous immunoglobulin for many years before the correct diagnosis is made.1 This case report describes the unique role of a pediatric hematologist to facilitate multidisciplinary care and services for a child diagnosed with MYH9-related disorder and illustrates the complex health care needs of this rare diagnosis in the pediatric populations. Case description: A 4-year-old girl of Mexican origin with a history of bilateral hearing loss and speech delay was first evaluated by audiology. Upon referral for a genetic evaluation, she was incidentally found to have asymptomatic thrombocytopenia. In the next four months, she received an extensive hematologic and infectious disease workup for the unexplained thrombocytopenia, while she was treated simultaneously for immune thrombocytopenia with corticosteroids or intravenous IgG. Neither of the interventions helped to normalize her persistently low platelet count (6,000-31,000), but instead led to sporadic intervals of undesirable weight gain and mood irritability. Further genetic testing with whole genome sequencing revealed a heterozygous pathogenic variant of MYH-9 mutation in the patient, who inherited the polymorphism from her father. Specifically, her variant exhibits complete penetrance for early-onset renal failure. As a result of the patient's platelet disorder and her frequent clinic visits to hematology, a close physician-patient relationship was developed thereafter. Her pediatric hematologist assumes the role of a primary care provider and coordinates multiple specialist visits to address her complex health care issues, including general pediatrics, speech therapy, audiology, otolaryngology, nephrology and medical genetics. Longitudinal care for this patient is mostly supportive: (1) platelet transfusion is required if she experiences any prolonged bleeding episodes; (2) prophylaxis with desmopressin is provided for dental and surgical procedures; (3) parents are counseled on child safety and limitations on major contact sports. Lastly, due to the identification of a pathogenic variant in both the patient and father, patient's brother and sister are both at increased risk of inheriting the platelet disorder. In our patient's case, since her family is limited by financial means for an evaluation with molecular testing, her siblings' platelet counts and sizes can be assessed instead with a CBC and peripheral blood smear. Discussion: The complexity of an inherited hematologic disorder involves multidisciplinary, longitudinal and lifelong care for optimal health care delivery and improved clinical outcomes. When approaching a pediatric patient diagnosed with a rare platelet disorder, the role of a hematologist becomes essential to be the primary care provider and to coordinate specialist visits for the patient without delays. Efficient care coordination with a focus on the patient's needs can avoid unnecessary duplication of tests and services.2 Children affected by rare genetic disorders, such as MYH-9 disorders, have complex unmet health needs and frequently experience unique barriers to care. Longitudinal surveillance is necessary to assess the progress of the MYH9 disease, and supportive care should be provided accordingly. References: Althaus, Karina, Greinacher, Andreas. MYH-9 Related Platelet Disorders: Strategies for Management and Diagnosis. Transfus Med Hemother, 2010 Lippe, Charlotte Von Der, et al. "Living with a Rare Disorder: a Systematic Review of the Qualitative Literature." Molecular Genetics & Genomic Medicine, vol. 5, no. 6, 2017, pp. 758-773., doi:10.1002/mgg3.315. Disclosures No relevant conflicts of interest to declare.
24
Puy, Hervé, Karim Zoubida, Lyoumi Said, Lydie M. Da Costa, and Gouya Laurent. "Heme-Related Blood Disorders." Blood 122, no. 21 (November 15, 2013): SCI—18—SCI—18. http://dx.doi.org/10.1182/blood.v122.21.sci-18.sci-18.
Full textAbstract:
Abstract Heme biosynthesis in erythroid cells is intended primarily for the formation of hemoglobin. As in every cell, this synthesis requires a multi-step pathway that involves eight enzymes including the erythroid-specific δ-aminolevulinate synthase (ALAS2, the first regulated enzyme that converts glycine and succinyl CoA into ALA) and the ubiquitous ferrochelatase (FECH, the final enzyme). Heme biosynthesis also requires membrane transporters that are necessary to translocate glycine, precursors of heme, and heme itself between the mitochondria and the cytosol. Defects in normal porphyrin and/or heme synthesis and transport cause four major erythroid inherited disorders, which may or may not be associated with dyserythropoiesis (e.g., sideroblastic, microcytic anemia and/or hemolytic anemia): "X-linked" sideroblastic anemia (XLSA) and X-linked dominant protoporphyria (XLDPP) are two different and opposing disorders but related to altered gene encoding ALAS2 only. Defective activity of this enzyme due to mutations in the ALAS2 gene causes the XLSA phenotype, including microcytic, hypochromic anemia with abundant ringed sideroblasts in the bone marrow. Vice versa, gain-of-function mutations of ALAS2 are responsible of the XLDPP characterized by predominant accumulation of the hydrophobic protoporphyrin (PPIX, the last heme precursor) in the erythrocytes without anemia or sideroblasts. Furthermore, the glycine transporter (SLC25A38) and Glutaredoxin 5 genes are reported to be involved in human non-syndromic sideroblastic anemia. Congenital erythropoietic porphyria (CEP) is the rarest autosomal recessive disorder due to a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. CEP leads to excessive synthesis and accumulation of type I isomers of porphyrins in the reticulocytes, followed by intravascular hemolysis and severe anemia. The ALAS2 gene may act as a modifier gene in CEP patients (Figueras J et al, Blood. 2011;118(6):1443-51). Erythropoietic protoporphyria (EPP) results from a partial deficiency of FECH and leads similarly to XLDPP, to deleterious accumulation of PPIX in erythroid cells. Most EPP patients present intrans to a FECH gene mutation an IVS3-48C hypomorphic allele due to a splice mutation. Abnormal spliced mRNA is degraded which contributes to the lowest FECH enzyme activity and allowed EPP phenotype expression. We have identified an antisense oligonucleotide (ASO) to redirect splicing from cryptic to physiological site and showed that the ASO-based therapy mediates normal splice rescue of FECH mRNA and reduction by 60 percent of PPIX overproduction in primary cultures of EPP erythroid progenitors. Therapeutic approaches to target both ALAS2 inhibition and heme-level reduction may be useful in other erythroid disorders such as thalassemia (where reduced heme biosynthesis was shown to improve the clinical phenotype) or the Diamond-Blackfan anemia (DBA). Indeed, in some DBA patients, an unusual mRNA splicing of heme exporter FLVCR has been found, reminiscent of Flvcr1-deficient mice that develop a DBA-like phenotype with erythroid heme accumulation. Thus, FLVCR may act as a modifier gene for DBA phenotypic variability. Recent advances in understanding the pathogenesis and molecular genetic heterogeneity of heme-related disorders have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias and some porphyrins and heme transporters, new understanding of the pathogenesis of the erythropoietic disorders, and new and experimental treatments such as chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for erythropoietic porphyrias. Disclosures: No relevant conflicts of interest to declare.
25
Dovzhenko, T. V., D. M. Tsarenko, and T. Yu Yudeeva. "Risk Factors and Chronicity of Bipolar Affective Disorder: Biological and Psychosocial Aspects." Консультативная психология и психотерапия 27, no. 4 (2019): 81–97. http://dx.doi.org/10.17759/cpp.2019270406.
Full textAbstract:
The literature review provides the results of epidemiological studies of bipolar affective disorder (BAD). Biological risk factors and adverse course of BAD are considered in detail, including genetic ones (BAD is defined as a genetically determined disorder that has common non-specific genetic risk factors with depressive and schizophrenic spectrum disorders). We address the data on various neurotransmitter systems dysfunctions that may play a role in the pathogenesis of the disease. The results of studies of biological markers in the blood, as well as morphological disorders in brain structures, are analyzed. Stressful situations, that can aggravate manifestations of a genetic and biochemical predisposition, disturbances in emotional and cognitive mental processes, neurocognitive deficiency, and dysfunctional family relationships are considered as psychosocial factors of BAD.
26
Zaninetti, Carlo, and Andreas Greinacher. "Diagnosis of Inherited Platelet Disorders on a Blood Smear." Journal of Clinical Medicine 9, no. 2 (February 17, 2020): 539. http://dx.doi.org/10.3390/jcm9020539.
Full textAbstract:
Inherited platelet disorders (IPDs) are rare diseases featured by low platelet count and defective platelet function. Patients have variable bleeding diathesis and sometimes additional features that can be congenital or acquired. Identification of an IPD is desirable to avoid misdiagnosis of immune thrombocytopenia and the use of improper treatments. Diagnostic tools include platelet function studies and genetic testing. The latter can be challenging as the correlation of its outcomes with phenotype is not easy. The immune-morphological evaluation of blood smears (by light- and immunofluorescence microscopy) represents a reliable method to phenotype subjects with suspected IPD. It is relatively cheap, not excessively time-consuming and applicable to shipped samples. In some forms, it can provide a diagnosis by itself, as for MYH9-RD, or in addition to other first-line tests as aggregometry or flow cytometry. In regard to genetic testing, it can guide specific sequencing. Since only minimal amounts of blood are needed for the preparation of blood smears, it can be used to characterize thrombocytopenia in pediatric patients and even newborns further. In principle, it is based on visualizing alterations in the distribution of proteins, which result from specific genetic mutations by using monoclonal antibodies. It can be applied to identify deficiencies in membrane proteins, disturbed distribution of cytoskeletal proteins, and alpha as well as delta granules. On the other hand, mutations associated with impaired signal transduction are difficult to identify by immunofluorescence of blood smears. This review summarizes technical aspects and the main diagnostic patterns achievable by this method.
27
Dudley, C. R., L. A. Giuffra, and S. T. Reeders. "Identifying genetic determinants in human essential hypertension." Journal of the American Society of Nephrology 3, no. 4 (October 1992): S2. http://dx.doi.org/10.1681/asn.v34s2.
Full textAbstract:
Genetic factors play an important role in the pathophysiology of human essential hypertension. The remarkable success of molecular genetic techniques in identifying the basis for single gene disorders at the DNA level has encouraged investigators to apply similar techniques in an attempt to identify blood pressure genes. In contrast to single gene disorders, however, the study of blood pressure is complicated by its quantitative, complex, heterogeneous, and polygenic nature. This article examines current methods and strategies for identifying genetic determinants in human hypertension. The availability of highly polymorphic markers, the advances in quantitative trait analysis, and the mapping of blood pressure-determining genes in a polygenic rat model of hypertension suggest that molecular genetic research in human hypertension has come of age.
28
Nathan, David G. "A Life-Long Quest to Understand and Treat Genetic Blood Disorders." Cell 143, no. 1 (October 2010): 17–20. http://dx.doi.org/10.1016/j.cell.2010.09.015.
Full text
29
Skoda, Radek. "The Genetic Basis of Myeloproliferative Disorders." Hematology 2007, no. 1 (January 1, 2007): 1–10. http://dx.doi.org/10.1182/asheducation-2007.1.1.
Full textAbstract:
AbstractFor many decades, myeloproliferative disorders (MPD) were largely neglected orphan diseases. The conceptual work of William Dameshek in 1951 provided the basis for understanding MPD as a continuum of related syndromes, possibly with a common pathogenetic cause. Recognition of the clonal origin of peripheral blood cells in MPD in 1976 and the ability to grow erythroid colonies in vitro in the absence of added growth factors in 1974 initiated the search for genetic alterations that might be responsible for myeloproliferation. Mutations in the genes for the erythropoietin receptor, thrombopoietin and the von Hippel–Lindau protein were found to cause familial syndromes resembling MPD, but despite their phenotypic similarities, none of these mutations were later found in patients with the sporadic form of MPD. The discovery of activating mutations in the Janus kinase 2 (JAK2) in most patients with MPD has fully transformed and energized the MPD field. Sensitive assays for detecting the JAK2-V617F mutation have become an essential part of the diagnostic work-up, and JAK2 now constitutes a prime target for developing specific inhibitors for the treatment of patients with MPD. Despite this progress, many questions remain unsolved, including how a single JAK2 mutation causes three different MPD phenotypes, what other genes might be involved in the pathogenesis, and what are the factors determining the progression to acute leukemia.
30
Risinger, Mary, and Theodosia A. Kalfa. "Red cell membrane disorders: structure meets function." Blood 136, no. 11 (September 10, 2020): 1250–61. http://dx.doi.org/10.1182/blood.2019000946.
Full textAbstract:
Abstract The mature red blood cell (RBC) lacks a nucleus and organelles characteristic of most cells, but it is elegantly structured to perform the essential function of delivering oxygen and removing carbon dioxide from all other cells while enduring the shear stress imposed by navigating small vessels and sinusoids. Over the past several decades, the efforts of biochemists, cell and molecular biologists, and hematologists have provided an appreciation of the complexity of RBC membrane structure, while studies of the RBC membrane disorders have offered valuable insights into structure–function relationships. Within the last decade, advances in genetic testing and its increased availability have made it possible to substantially build upon this foundational knowledge. Although disorders of the RBC membrane due to altered structural organization or altered transport function are heterogeneous, they often present with common clinical findings of hemolytic anemia. However, they may require substantially different management depending on the underlying pathophysiology. Accurate diagnosis is essential to avoid emergence of complications or inappropriate interventions. We propose an algorithm for laboratory evaluation of patients presenting with symptoms and signs of hemolytic anemia with a focus on RBC membrane disorders. Here, we review the genotypic and phenotypic variability of the RBC membrane disorders in order to raise the index of suspicion and highlight the need for correct and timely diagnosis.
31
de Jong, Simone, Stephen J. Newhouse, Hamel Patel, Sanghyuck Lee, David Dempster, Charles Curtis, Jose Paya-Cano, et al. "Immune signatures and disorder-specific patterns in a cross-disorder gene expression analysis." British Journal of Psychiatry 209, no. 3 (September 2016): 202–8. http://dx.doi.org/10.1192/bjp.bp.115.175471.
Full textAbstract:
BackgroundRecent studies point to overlap between neuropsychiatric disorders in symptomatology and genetic aetiology.AimsTo systematically investigate genomics overlap between childhood and adult attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and major depressive disorder (MDD).MethodAnalysis of whole-genome blood gene expression and genetic risk scores of 318 individuals. Participants included individuals affected with adult ADHD (n = 93), childhood ADHD (n = 17), MDD (n = 63), ASD (n = 51), childhood dual diagnosis of ADHD–ASD (n = 16) and healthy controls (n = 78).ResultsWeighted gene co-expression analysis results reveal disorder-specific signatures for childhood ADHD and MDD, and also highlight two immune-related gene co-expression modules correlating inversely with MDD and adult ADHD disease status. We find no significant relationship between polygenic risk scores and gene expression signatures.ConclusionsOur results reveal disorder overlap and specificity at the genetic and gene expression level. They suggest new pathways contributing to distinct pathophysiology in psychiatric disorders and shed light on potential shared genomic risk factors.
32
Ruszkowska, Hanna, Magdalena Lewicka, Magdalena Sulima, Grzegorz Bakalczuk, Anna Taracha, and Artur Wdowiak. "Characteristics of Menstrual Disorders." Pielegniarstwo XXI wieku / Nursing in the 21st Century 17, no. 2 (June 1, 2018): 27–31. http://dx.doi.org/10.2478/pielxxiw-2018-0012.
Full textAbstract:
Abstract Introduction. The structure was based on the World Health Organisation classification. The article includes description of main causes, diagnostics and treatment of menstrual disorders. Menstrual disorder is an abnormal condition in woman’s menstrual cycle. There are disorders of ovulation, cycle length, blood flow and others. The article reviews hypogonadotropic hypogonadism, disorders of hypothalamic pituitary axis, ovarian insufficiency, congenital malformations, hyperprolactinaemia, genetic syndromes, pituitary gland tumours and unclassified disorders like premenstrual syndrome and dysmenorrhoea. Aim. Analysis of current literature with the focus on the systematisation of menstrual disorders. Conclusion. It is crucial for medical practitioners, who take care of a female patient, to have reliable knowledge of not only physiology, but also menstrual disorders. It will allow an early recognition of the symptoms, proper diagnosis and treatment in the optimal time.
33
Gallagher, Patrick G. "Disorders of erythrocyte hydration." Blood 130, no. 25 (December 21, 2017): 2699–708. http://dx.doi.org/10.1182/blood-2017-04-590810.
Full textAbstract:
Abstract The erythrocyte contains a network of pathways that regulate salt and water content in the face of extracellular and intracellular osmotic perturbations. This allows the erythrocyte to maintain a narrow range of cell hemoglobin concentration, a process critical for normal red blood cell function and survival. Primary disorders that perturb volume homeostasis jeopardize the erythrocyte and may lead to its premature destruction. These disorders are marked by clinical, laboratory, and physiologic heterogeneity. Recent studies have revealed that these disorders are also marked by genetic heterogeneity. They have implicated roles for several proteins, PIEZO1, a mammalian mechanosensory protein; GLUT1, the glucose transporter; SLC4A1, the anion transporter; RhAG, the Rh-associated glycoprotein; KCNN4, the Gardos channel; and ABCB6, an adenosine triphosphate–binding cassette family member, in the maintenance of erythrocyte volume homeostasis. Secondary disorders of erythrocyte hydration include sickle cell disease, thalassemia, hemoglobin CC, and hereditary spherocytosis, where cellular dehydration may be a significant contributor to disease pathology and clinical complications. Understanding the pathways regulating erythrocyte water and solute content may reveal innovative strategies to maintain normal volume in disorders associated with primary or secondary cellular dehydration. These mechanisms will serve as a paradigm for other cells and may reveal new therapeutic targets for disease prevention and treatment beyond the erythrocyte.
34
Leebeek, Frank W. G., Johannes Duvekot, and Marieke J. H. A. Kruip. "How I manage pregnancy in carriers of hemophilia and patients with von Willebrand disease." Blood 136, no. 19 (November 5, 2020): 2143–50. http://dx.doi.org/10.1182/blood.2019000964.
Full textAbstract:
Abstract Women with inherited bleeding disorders, including carriers of hemophilia A and B, or with von Willebrand disease, have an increased risk of bleeding during pregnancy and delivery. The unborn child may also be affected by the bleeding disorder for which specific measures have to be considered. This requires a multidisciplinary approach, with a team that includes a hematologist, a pediatric hematologist, a clinical geneticist, an obstetrician-perinatologist, and an anesthesiologist. An optimal approach includes prepregnancy genetic counseling, prenatal diagnostic procedures, and a treatment plan for delivery for both the mother and child. Recent retrospective studies show that even if strict guidelines are followed, these women are still at risk of postpartum bleeding. This occurs even if coagulation factor levels are normalized, either due to the pregnancy-induced rise of factor levels or by infusion of coagulation factor concentrates at the time of delivery. In this article, we describe our current diagnostic and clinical management of pregnancy and delivery in women with inherited bleeding disorders. We also briefly discuss possible interventions to improve the outcome of current strategies by increasing target factor levels during and after delivery.
35
Papanikolaou, George, Michalis Tzilianos, John I. Christakis, Dionisios Bogdanos, Konstantina Tsimirika, Julie MacFarlane, Y. Paul Goldberg, Nikos Sakellaropoulos, Tomas Ganz, and Elizabeta Nemeth. "Hepcidin in iron overload disorders." Blood 105, no. 10 (May 15, 2005): 4103–5. http://dx.doi.org/10.1182/blood-2004-12-4844.
Full textAbstract:
Abstract Hepcidin is the principal regulator of iron absorption in humans. The peptide inhibits cellular iron efflux by binding to the iron export channel ferroportin and inducing its internalization and degradation. Either hepcidin deficiency or alterations in its target, ferroportin, would be expected to result in dysregulated iron absorption, tissue maldistribution of iron, and iron overload. Indeed, hepcidin deficiency has been reported in hereditary hemochromatosis and attributed to mutations in HFE, transferrin receptor 2, hemojuvelin, and the hepcidin gene itself. We measured urinary hepcidin in patients with other genetic causes of iron overload. Hepcidin was found to be suppressed in patients with thalassemia syndromes and congenital dyserythropoietic anemia type 1 and was undetectable in patients with juvenile hemochromatosis with HAMP mutations. Of interest, urine hepcidin levels were significantly elevated in 2 patients with hemochromatosis type 4. These findings extend the spectrum of iron disorders with hepcidin deficiency and underscore the critical importance of the hepcidin–ferroportin interaction in iron homeostasis.
36
Al Arrayed, S., N. Hafadh, S. Amin, H. Al Mukhareq, and H. Sanad. "Student screening for inherited blood disorders in Bahrain." Eastern Mediterranean Health Journal 9, no. 3 (September 1, 2021): 344–52. http://dx.doi.org/10.26719/2003.9.3.344.
Full textAbstract:
In Bahrain and neighbouring countries inherited disorders of haemoglobin, i. e. sickle-cell disease, thalassaemias and glucose-6-phosphate dehydrogenase [G6PD] deficiency, are common. As part of the National Student Screening Project to determine the prevalence of genetic blood disorders and raise awareness among young Bahrainis, we screened 11th-grade students from 38 schools [5685 students], organized lectures and distributed information about these disorders. Haemoglobin electrophoresis, high performance liquid chromatography, blood grouping and G6PD deficiency testing were performed. Prevalences were: 1.2% sickle-cell disease; 13.8% sickle-cell trait; 0.09% beta-thalassaemia; 2.9% beta-thalassaemia trait; 23.2% G6PD deficiency; 1.9% G6PD deficiency carrier. Health education, carrier screening and premarital counselling remain the best ways to reduce disease incidence with potentially significant financial savings and social and health benefits
37
Hamada, Motoharu, Hideki Muramatsu, Yusuke Okuno, Ayako Yamamori, Taro Yoshida, Masayuki Imaya, Manabu Wakamatsu, et al. "Diagnostic Whole Exome Sequencing for 166 Patients with Inherited Bone Marrow Failure Syndrome." Blood 136, Supplement 1 (November 5, 2020): 9. http://dx.doi.org/10.1182/blood-2020-143241.
Full textAbstract:
BACKGROUND: Inherited bone marrow failure syndromes (IBMFSs) are a heterogeneous group of genetic disorders characterized by bone marrow failure, physical anomalies, and various kinds of organ complications. In addition to classical IBMFSs, such as Fanconi anemia, Diamond-Blackfan anemia, Dyskeratosis congenita, Shwachman-Diamond syndrome, and familial platelet disorders, many types of unclassified IBMFSs are reported. Over 100 genes are considered causative genes; however, the precise genetic diagnosis of IBMFSs remains challenging. We developed a capture-based target sequencing method for IBMFSs that covers more than 180 associated genes. Our system achieved genetic diagnosis for 225 (35%) of 738 patients between 2013 and 2018. However, the causative gene remained unknown for 513 (65%) patients, and further genetic analysis of these "target-negative" cases was necessary to achieve a precise diagnosis. METHODS: We performed whole exome sequencing (WES) for patients who were "target-negative" but strongly suspected of having IBMFS based on the following clinical characteristics: physical or organ anomalies (skin, nail, hair, skeletal, growth, cardiac, lung, liver, or genitourinary), family history of hematological disorder, young age (≤2 years), short telomere length (<-2.0 SD), and hyper sensitivity to the chromosome breakage test. A sequencing library was prepared using the SureSelect Human All Exon 50Mb kit (Agilent Technologies, Santa Clara, CA, USA) and it was sequenced using the HiSeq2000 platform (Illumina, San Diego, CA, USA), according to manufacturers' instructions. The candidate germline variants were detected through our Genomon-exome analysis pipeline. With mean coverage of 100×, ≥ 85% of all protein coding bases were covered at 20× or more. RESULTS: Among the 513 "target-negative" cases, 166 patients were evaluated, of whom 17 patients' parents were also analyzed in a trio-based analysis. New pathogenic variants were identified in 18 of the 166 (11%) patients according to the American College of Medical Genetics (ACMG) guidelines, of which 5 variants were revealed to be de novo. Diagnostic variants were identified in FANCF, SRP54, RPL19, RPL5, RTEL1, RUNX1, MECOM, CDC42, GNE, SLNF14 (all n = 1). In addition to IBMFS-associated genes, causative genes for congenital hemolytic anemia (G6PD, PKLR), inborn error of metabolism (SLC46A1), and primary immune deficiency (NFKB2, LRBA) are also identified (all n = 1). Moreover, loss-of-function mutation of ADH5 gene are identified in three patients that seems to be associated to novel IBMFSs. On the other hand, no pathogenic variant in GATA2, ERCC6L2, LIG4, and SAMD9/SAMD9L genes that are reported as unclassified IBMFSs in Europe and United States are identified in our cohort. CONCLUSION: Our findings support the utility of WES (especially trio-based analysis) as a diagnostic tool for IBMFSs. Furthermore, genetic background of IBMFSs in East Asia seems to be different from that of Europe and United States. Disclosures No relevant conflicts of interest to declare.
38
Ng, Ashley P., Craig D. Hyland, Donald Metcalf, Catherine L. Carmichael, Stephen J. Loughran, Ladina Di Rago, Benjamin T. Kile, and Warren S. Alexander. "Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome." Blood 115, no. 19 (May 13, 2010): 3966–69. http://dx.doi.org/10.1182/blood-2009-09-242107.
Full textAbstract:
Abstract Down syndrome is characterized by multiple phenotypic manifestations associated with trisomy of chromosome 21. The transient myeloproliferative disorder and acute megakaryocytic leukemia associated with Down syndrome are uniquely associated with mutations in the transcription factor GATA1; however, the identity of trisomic genes on chromosome 21 that predispose to these hematologic disorders remains unknown. Using a loss-of-function allele, we show that specific reduction to functional disomy of the Erg gene corrects the pathologic and hematologic features of myeloproliferation in the Ts(1716)65Dn mouse model of Down syndrome, including megakaryocytosis and progenitor cell expansion. Our data provide genetic evidence establishing the need for Erg trisomy for myeloproliferation in Ts(1716)65Dn mice and imply that increased ERG gene dosage may be a key consequence of trisomy 21 that can predispose to malignant hematologic disorders in Down syndrome.
39
Tiacci, Enrico, Gianluca Schiavoni, Francesco Forconi, Alessia Santi, Livio Trentin, Achille Ambrosetti, Debora Cecchini, et al. "Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation." Blood 119, no. 1 (January 5, 2012): 192–95. http://dx.doi.org/10.1182/blood-2011-08-371179.
Full textAbstract:
Abstract Hairy cell leukemia (HCL) is a distinct clinicopathologic entity that responds well to purine analogs but is sometimes difficult to differentiate from HCL-like disorders (eg, splenic marginal zone lymphoma and HCL variant). We recently identified the BRAF-V600E mutation as the disease-defining genetic event in HCL. In this study, we describe a new, simple, and inexpensive test for genetics-based diagnosis of HCL in whole-blood samples that detects BRAF-V600E through a sensitive allele-specific PCR qualitative assay followed by agarose-gel electrophoresis. This approach detected BRAF-V600E in all 123 leukemic HCL samples investigated containing as few as 0.1% leukemic cells. BRAF-V600E was detected at different time points during the disease course, even after therapy, pointing to its pivotal role in HCL pathogenesis and maintenance of the leukemic clone. Conversely, 115 non-HCL chronic B-cell neoplasms, including 79 HCL-like disorders, were invariably negative for BRAF-V600E. This molecular assay is a powerful tool for improving the diagnostic accuracy in HCL.
40
Pei, Lulu X., Tebogo T. Leepile, Kelsey M. Cochrane, Kaitlyn L. I. Samson, Jordie A. J. Fischer, Brock A. Williams, Hou Kroeun, Lizl Bonifacio, and Crystal D. Karakochuk. "Can Automated Hematology Analyzers Predict the Presence of a Genetic Hemoglobinopathy? An Analysis of Hematological Biomarkers in Cambodian Women." Diagnostics 11, no. 2 (February 3, 2021): 228. http://dx.doi.org/10.3390/diagnostics11020228.
Full textAbstract:
Genetic hemoglobinopathies are the most common single-gene disorder worldwide. Some automated hematology analyzers have the capability of flagging individuals who may have hematological disorders based on complete blood count (CBC) biomarkers. We aimed to evaluate the accuracy of a hematology analyzer in identifying genetic hemoglobinopathies in Cambodian women and to determine which hematological biomarkers are the best predictors. A CBC was completed using a Sysmex XN-1000 analyzer and hemoglobinopathies were determined with capillary hemoglobin electrophoresis for 808 nonpregnant Cambodian women. Sysmex XN-1000 Interpretive Program (IP) messages, which flag potential hematological disorders, were produced from CBC results. Then, 2 × 2 tables were used to determine sensitivity and specificity of the IP message “Hemoglobin defect” to detect a genetic hemoglobinopathy. Receiver operating characteristic (ROC) analyses assessed the diagnostic ability of six CBC biomarkers to predict a genetic hemoglobinopathy. In total, 74% of women had a hemoglobinopathy (predominantly Hb E and α-thalassemia). “Hb defect” IP message sensitivity and specificity for genetic hemoglobinopathy detection were 10.4% and 98.6%, respectively. Variable selection strategies yielded a two-variable model including mean corpuscular volume (MCV) and red blood cell (RBC) count (AIC = 99.83, AUCROC = 0.98 (95% CI: 0.97, 0.99)) for the prediction of a homozygous EE disorder. Sensitivity and specificity values do not justify the use of Sysmex XN-1000 IP flag messages for identification of genetic hemoglobinopathies in Cambodian women. Development of an algorithm based on MCV and RBC biomarkers may optimize the screening ability of automated hematology analyzers.
41
Wilcox, David A. "Megakaryocyte- and megakaryocyte precursor–related gene therapies." Blood 127, no. 10 (March 10, 2016): 1260–68. http://dx.doi.org/10.1182/blood-2015-07-607937.
Full textAbstract:
Abstract Hematopoietic stem cells (HSCs) can be safely collected from the body, genetically modified, and re-infused into a patient with the goal to express the transgene product for an individual’s lifetime. Hematologic defects that can be corrected with an allogeneic bone marrow transplant can theoretically also be treated with gene replacement therapy. Because some genetic disorders affect distinct cell lineages, researchers are utilizing HSC gene transfer techniques using lineage-specific endogenous gene promoters to confine transgene expression to individual cell types (eg, ITGA2B for inherited platelet defects). HSCs appear to be an ideal target for platelet gene therapy because they can differentiate into megakaryocytes which are capable of forming several thousand anucleate platelets that circulate within blood vessels to establish hemostasis by repairing vascular injury. Platelets play an essential role in other biological processes (immune response, angiogenesis) as well as diseased states (atherosclerosis, cancer, thrombosis). Thus, recent advances in genetic manipulation of megakaryocytes could lead to new and improved therapies for treating a variety of disorders. In summary, genetic manipulation of megakaryocytes has progressed to the point where clinically relevant strategies are being developed for human trials for genetic disorders affecting platelets. Nevertheless, challenges still need to be overcome to perfect this field; therefore, strategies to increase the safety and benefit of megakaryocyte gene therapy will be discussed.
42
Pietra, Daniela, Sai Li, Angela Brisci, Francesco Passamonti, Elisa Rumi, Alexandre Theocharides, Maurizio Ferrari, et al. "Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders." Blood 111, no. 3 (February 1, 2008): 1686–89. http://dx.doi.org/10.1182/blood-2007-07-101576.
Full textAbstract:
Abstract We searched for JAK2 exon 12 mutations in patients with JAK2 (V617F)-negative myeloproliferative disorders. Seventeen patients with polycythemia vera (PV), including 15 sporadic cases and 2 familial cases, carried deletions or duplications of exon 12 in circulating granulocytes but not in T lymphocytes. Two of the 8 mutations detected were novel, and the most frequent ones were N542-E543del and E543-D544del. Most patients with PV carrying an exon 12 mutation had isolated erythrocytosis at clinical onset, unlike patients with JAK2 (V617F)-positive PV, most of whom had also elevations in white blood cell and/or platelet counts. Both patients with familial PV carrying an exon 12 mutation had an affected sibling with JAK2 (V617F)-positive PV. Thus, several somatic mutations of JAK2 exon 12 can be found in a myeloproliferative disorder that is mainly characterized by erythrocytosis. Moreover, a genetic predisposition to acquisition of different JAK2 mutations is inherited in families with myeloproliferative disorders.
43
DeRoin, Lia, Marcela Cavalcante De Andrade Silva, Kristin Petras, Kelly Arndt, Nathaniel Phillips, Pankhuri Wanjari, Hari Prasanna Subramanian, et al. "Assessing the Feasibility and Limitations of Cultured Skin Fibroblasts for Germline Genetic Testing in Hematologic Disorders." Blood 136, Supplement 1 (November 5, 2020): 35–36. http://dx.doi.org/10.1182/blood-2020-138431.
Full textAbstract:
Introduction Peripheral blood is the standard tissue source for germline genetic testing in most scenarios. In patients with hematologic malignancies, however, peripheral blood frequently contains tumor- or clonal hematopoiesis-related acquired genetic variants, often occurring in genes that can also cause inherited cancer susceptibility if present in the germline. Thus, an alternative tissue source is necessary. Cultured skin fibroblasts have been used as a potentially ideal alternative because they are free from blood contamination and provide ample DNA yields, advantages that other alternatives such as saliva or nail clippings lack. However, optimal culture methods, expected time from biopsy to sufficient DNA yield, culture failure rate, and limitations of this technique, including the possibility of variants being acquired solely due to the culturing process, are not yet known. Methods We conducted a retrospective cohort study of subjects with cytopenias or hematologic malignancies who underwent skin biopsy and fibroblast culture for germline genetic testing from April 2014 to June 2018. Skin biopsy culture technical data, including time from biopsy to culture set-up, shipment from an outside institution, culture failure, and biopsy size, were abstracted from tissue culture logs. Patient demographics, comorbidities, medication history, and hematologic diagnosis and treatment were abstracted from medical records. Next generation sequencing data from targeted capture of 144 inherited cancer and bone marrow failure predisposition genes obtained for clinical genetic testing purposes were analyzed to identify variants at both germline (40-60%) and subclonal (10-40%) variant allele frequencies (VAF). Pathogenicity was interpreted according to ACMG/AMP guidelines. Fisher's exact tests and logistic regression models were used to assess associations with culture failure. T-tests and linear regression models were used to assess factors associated with mean time to confluency. Results In total, we studied 350 samples from unique patients, including 61 (24%) who carried one or more pathogenic or likely pathogenic cancer susceptibility gene variant(s). Overall, 16 of the 350 (5%) biopsies failed to grow in culture. The median time from skin biopsy to sufficient growth to extract DNA for genetic testing was 27 days (IQR 22-29 days). Culture failure was significantly more likely in samples with a delay in culture initiation for 24 hours post biopsy (OR=4.32; p<0.01), and a pathogenic germline variant in a gene associated with telomere maintenance (OR=64.50; p<0.01). Factors associated with an increased mean time to sufficient growth included prior allogeneic stem cell transplant (32.1 days versus 27.2 days; p<0.01) and prior intravenous (IV) steroid exposure (29.9 days versus 26.4 days; p<0.01). Among samples cultured successfully, carriers of any pathogenic germline variant had a significantly decreased mean time to sufficient growth (25.4 days versus 28.6 days; p<0.01). A pathogenic or likely pathogenic subclonal variant was identified in 11 (4%) subjects at a median VAF of 20%. Among eight of these with additional tissue available, the presence of the variant was confirmed in four (50%). In individual cases, we found evidence of loss of a pathogenic variant in the hematopoietic malignancy. In one patient with a pathogenic variant with a 50% VAF in the original skin culture, the variant was not present in a skin culture from a second, fresh skin biopsy done due to discordant phenotype. Conclusions Culturing of skin fibroblasts for germline genetic testing in patients with hematologic disorders has a high success rate, especially when cultures are initiated within 24 hours of collection, and adds on average 27 days to genetic testing turnaround time. From patients with a hereditary syndrome, most skin biopsies will culture with the exception of individuals with a short telomere syndrome. For this subset, a direct skin biopsy without culture may be necessary. Subclonal variants at VAFs relevant to interpretation of a germline test were found in 4% of cases. Half were confirmed in an alternative tissue. Etiology of the subclonal variants, whether acquired during the culturing process or due to mosaicism or sequencing biases was not always clear. Careful assessment of the clinical phenotype in interpreting and applying germline genetic results to patient care will always be warranted. Disclosures Godley: UptoDate, Inc.: Honoraria; Invitae, Inc.: Membership on an entity's Board of Directors or advisory committees. Segal:BMS: Consultancy, Research Funding; AbbVie: Consultancy; Merck: Consultancy; Astra Zeneca: Consultancy. Churpek:UpToDate, Inc: Honoraria.
44
Edmonds, Liza K., Barbara J. Mosley, Anita J. Admiraal, Robin J. Olds, Sarah E. Romans, Trevor Silverstone, and Anne E. S. Walsh. "Familial Bipolar Disorder: Preliminary Results from the Otago Familial Bipolar Genetic Study." Australian & New Zealand Journal of Psychiatry 32, no. 6 (December 1998): 823–29. http://dx.doi.org/10.3109/00048679809073872.
Full textAbstract:
Objective: This paper outlines the methodologies used, and preliminary descriptive data collected, on a cohort of familial bipolar disorder (BPD) probands and first-degree relatives taking part in a descriptive and genetic study into familial BPD in New Zealand. Method: Fifity-five bipolar probands and 67 first-degree relatives were interviewed using the modified Diagnostic Interview for Genetic Studies (DIGS) and Family Interview for Genetic Studies (FIGS). Data was also collated from other sources. Blood samples were taken for DNA genomic analysis. Results: New Zealand families in which BPD segregates proved willing participants in this familial based genetic research. The methodologies used were acceptable. High rates of comorbidity were found in probands (27.3% met DSM-IV criteria for panic disorder/sub-threshold panic disorder; 12.7% for phobic disorder; 1.8% for obsessive-compulsive disorder; 9.1% for alcohol-related disorders and 7.3% for an eating disorder) and relatives (major depression 34.3%; panic disorder/sub-threshold panic disorder 12.0%; phobias 11.9% and alcohol-related disorders 11.9%). The polarity of index BPD illness was related to age of onset and frequency of comorbidity. Suicidal behaviour was common. Conclusions: Psychiatric genetic research in New Zealand families is highly feasible. Emerging trends in the familial transmission of BPD include high rates of comorbidity, illness patterns based on polarity of index episode and frequent suicidal behaviour. Such trends will be delineated further as numbers accrue, perhaps enabling identification of more homogenous phenotypic subgroups than currently produced by diagnostic schemes.
45
Narla, Anupama, and Benjamin L. Ebert. "Ribosomopathies: human disorders of ribosome dysfunction." Blood 115, no. 16 (April 22, 2010): 3196–205. http://dx.doi.org/10.1182/blood-2009-10-178129.
Full textAbstract:
Abstract Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, Schwachman-Diamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q− syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases.
46
Pajovic, Snezana. "Polygenic and miltufactorial disorders." Genetika 39, no. 2 (2007): 283–90. http://dx.doi.org/10.2298/gensr0702283p.
Full textAbstract:
Many factors influence our susceptibility to disease. These include our stress load, our environment and the toxins we absorb from it, the total number of infectious agents we are exposed to as well as our underlying genetic susceptibility to these diseases. Multifactorial is the term given to the mode of transmission shown by a large number of diseases which show familial clustering but which is not in accord with any recognized pattern of single gene inheritance. These diseases include several common congenital malformations and acquired disorders of childhood and adult life. The underlying genetic mechanism is thought to involve interaction of relatively large numbers of genes - hence oligogenic or polygenic - with environmental factors. The ultimate cause of Alzheimer?s (AD) is unknown. Genetic factors are suspected, and dominant mutations in three different genes have been identified that account for a much smaller number of cases of familial, early -onset AD. For the more form of late onset AD, ApoE is the only repeatedly confirmed susceptibility gene. Coronary artery disease is well-recognized complication of several single-gene disorders involving lipid metabolism. Over 20 genes have been proposed as candidates for polygenic coronary artery disease. These include genes which control lipid metabolism, blood pressure, clotting, and fibrinolysis.
47
Simeoni, Ilenia, Jonathan C. Stephens, Fengyuan Hu, Sri V. V. Deevi, Karyn Megy, Tadbir K. Bariana, Claire Lentaigne, et al. "A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders." Blood 127, no. 23 (June 9, 2016): 2791–803. http://dx.doi.org/10.1182/blood-2015-12-688267.
Full textAbstract:
Key Points Developed a targeted sequencing platform covering 63 genes linked to heritable bleeding, thrombotic, and platelet disorders. The ThromboGenomics platform provides a sensitive genetic test to obtain molecular diagnoses in patients with a suspected etiology.
48
Hsia, David Yi-Yung. "Use of white blood cells and cultured somatic cells in clinical genetic disorders." Clinical Genetics 1, no. 1 (April 23, 2008): 5–14. http://dx.doi.org/10.1111/j.1399-0004.1970.tb01963.x.
Full text
49
Chachkin, Carolyn Jacobs. "What Potent Blood: Non-Invasive Prenatal Genetic Diagnosis and the Transformation of Modern Prenatal Care." American Journal of Law & Medicine 33, no. 1 (March 2007): 9–53. http://dx.doi.org/10.1177/009885880703300101.
Full textAbstract:
What potent blood hath modest May,What fiery force the earth renews,The wealth of forms, the flush of hues ….—Ralph Waldo EmersonSomeday soon, virtually any pregnant woman will be able to learn — with 98-99% accuracy — whether her fetus has contracted a serious genetic disorder by undergoing nothing more than an inexpensive, non-invasive blood test. For years, scientists have sought a method of prenatal testing that could boast both high levels of accuracy and low levels of risk. The most promising solution lies in an exciting recent discovery: tiny quantities of fetal cells and DNA cross over into the mother's bloodstream during pregnancy. If the fetal genetic material can be successfully isolated from the maternal blood, it can be used to diagnose a number of genetic disorders, such as Down Syndrome, cystic fibrosis, Tay-Sachs disease, and sickle cell anemia. Indeed, researchers have spent the last decade developing ways to accomplish this.
50
Freson, Kathleen. "Clinical Next Generation Sequencing to Identify Novel Platelet Disorders." Blood 128, no. 22 (December 2, 2016): SCI—38—SCI—38. http://dx.doi.org/10.1182/blood.v128.22.sci-38.sci-38.
Full textAbstract:
Abstract Inherited platelet disorders (IPDs) comprise a heterogeneous group of disorders with a complex genetic etiology, characterized by impairments in platelet formation, morphology and function. Since the implementation of next generation sequencing (NGS) in 2009, the gene list for diagnosis of IPDs rapidly expanded from 39 to 53 genes. A diagnostic high-throughput targeted NGS platform (referred to as ThromboGenomics; www.thrombogenomics.org.uk) was very recently described as an affordable DNA-based test of 76 genes to diagnose patients 'suspected of having a known inherited platelet, thrombotic or bleeding disorder' (BPD). When the phenotype is strongly indicative of the presence of a particular disease etiology but the variants are unknown, sensitivity remains high (>90% based on 61 samples) while patients included with an uncertain disease such as delta storage pool disease, mostly receive no genetic diagnosis (only 10% a genetic diagnosis was obtained). Such IPDs should be included in gene discovery NGS programs such as the BRIDGE-BPD2 study. For this study, whole genome sequencing results of the DNA samples of nearly 1000 probands with uncharacterized IPDs, analyzed using assigned Human Phenotype Ontology (HPO) terms have helped to identify pathogenic variants in almost 20% of cases. New clustering algorithms to group cases with similar phenotypes have been used to identify two novel IPD genes (DIAPH1 and SRC2) and several putative ones. Still many IPD patients don't receive a genetic diagnosis. A majority of cases either harbor pathogenic variants in unknown genes or in regulatory regions or are the result of a digenic mode of inheritance. NGS combined with data from RNA-seq, ChIP-seq, gene regulatory network analysis, epigenome, proteomics and mouse knock-out studies amongst others will also help explore the non-coding regulatory space and gene-gene interactions. Given the existence of many non-pathogenic variants in any individual's genome, the main challenge faced by researchers when interpreting NGS data of an IPD case is determining which variants are causing the disorder.3Interpreting the functional consequences of novel rare variants is not easy and it is extremely important to apply rigorous standards when assigning pathogenicity. Clinical genomic data are the same as other complex medical data and should be interpreted by a multidisciplinary team comprising typically a statistical geneticist, clinical geneticist, and genetic counselors, who have the skills to interpret these results in the context of the test methodology, the theoretical background of genetics, Bayesian reasoning, and a myriad of other factors. 1. Simeoni I, Stephens JC, Hu F, et al. A comprehensive high-throughput sequencing test for the diagnosis of inherited bleeding, thrombotic and platelet disorders. Blood. 2016; 127: 279. 2. Turro E, Greene D, Wijgaerts A, et al. A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies. Sci Transl Med. 2016;8:328. 3. Lentaigne C, Freson K, Laffan MA, et al. Inherited platelet disorders: towards DNA-based diagnosis. Blood. 2016; 127: 2814. Disclosures No relevant conflicts of interest to declare.