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WFH Treatment Guidelines 3Ed Chapter 4 Genetic Assessment

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WFH Treatment Guidelines 3Ed Chapter 4 Genetic Assessment 55 GENETIC 4 ASSESSMENT Megan Sutherland1 | Carlos De Brasi2 | Barbara A. Konkle3 | Shrimati Shetty4 | Glenn F. Pierce5 | Alok Srivastava6 1 Manchester University Hospitals NHS Foundation Trust, Manchester, UK 2 Sección Genética Molecular de la Hemofilia, Instituto de Investigaciones Hematologicas and Instituto de Medicina Experimental, CONICET – Academia Nacional de Medicina, Buenos Aires, Argentina 3 Bloodworks Northwest and Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, USA 4 ICMR – National Institute of Immunohaematology, KEM Hospital, Mumbai, India 5 World Federation of Hemophilia, Montreal, QC, Canada 6 Department of Haematology, Christian Medical College, Vellore, India All statements identified as recommendations are • Genetic testing will not always identify the underlying consensus based, as denoted by CB. variant associated with the hemophilia phenotype. Genetic counselling should highlight this possibility to the individual referred for genetic testing. (See Chapter 9: 4.1 Introduction Specific Management Issues – Carriers – Genetic counselling – Psychosocial support.) • Genetic assessment of hemophilia is important in defining • Genetic diagnostic laboratories should adhere to strict disease biology, establishing diagnosis in difficult cases, protocols and procedures, which require: predicting risk of inhibitor development, identifying female – knowledge and expertise in genetic laboratory carriers, and providing prenatal diagnosis, if desired.1 testing; • Genotype analysis should be offered to all people with – use of the correct investigative platforms; hemophilia and their “at-risk” female family members. – knowledge and expertise in the interpretation of • Genetic testing strategies are led by the phenotypic the genetic variants identified in association with parameters measured by the coagulation laboratory in hemophilia; addition to the family pedigree. Therefore, it is essential that – use of the correct interpretative platforms for the data are made available to the genetic testing laboratory. investigation of variants; An accurate interpretation of the underlying variant(s) – use of the correct nomenclature for description of detected is dependent on the supporting phenotypic data variants and the correct classification systems for and family history for the patient.2-5 determining pathogenicity of variants; • Genetic counselling for people with hemophilia and their – internal quality control procedures; families is an essential requirement prior to genetic testing. – participation in periodic accreditation, where This includes obtaining informed consent from the patient, available; and parent, or legal guardian, requiring both permission to – participation in external quality assessment schemes carry out testing as well as education to ensure that they (EQAS), where available. fully understand the testing procedure, the benefits and • The interpretation of the results of genetic testing should limitations of the test, and possible consequences of the be performed by scientists who have knowledge and test results.6,7 expertise in hemophilia genetics. • Genetic counselling should also provide information and • The opportunity for discussion of the genetic results advice about prenatal diagnosis (PND), management of between the ordering clinician and reporting scientist is pregnancy and delivery in hemophilia carriers, and pre- an essential provision of the genetic diagnostic service. implantation genetic diagnosis (PGD). It is important to be aware of and follow the relevant laws governing such RECOMMENDATION 4.1.1: procedures in the country where the service is being • For people with hemophilia, the WFH recommends provided. that genetic testing be offered to identify the specific 56 WFH Guidelines for the Management of Hemophilia, 3rd edition underlying genetic variant associated with their disorder. knowledge of genetics in hemophilia can provide genetic CB counselling. CB RECOMMENDATION 4.1.2: RECOMMENDATION 4.1.7: • For obligate carriers of hemophilia and “at-risk” female • For all patients referred for genetic testing, the WFH relatives of people with hemophilia or potential carriers strongly recommends that informed consent be obtained of hemophilia, the WFH recommends that genetic from the patient, parent, or legal guardian. This requires testing be offered for the previously identified genetic both permission to carry out testing and education to variant in the F8 or F9 gene. CB ensure that they fully understand the testing procedure, the benefits and limitations of the test, and possible RECOMMENDATION 4.1.3: consequences of the test results. • For females with low phenotypic coagulation FVIII or • REMARK: Written informed consent may need to be FIX levels, the WFH recommends that investigation obtained and documented by the clinician or genetic of the genetic/epigenetic basis of the phenotype be counsellor in compliance with local policies and practices. offered. CB CB RECOMMENDATION 4.1.4: • For obligate carriers of hemophilia and “at-risk” female 4.2 Indications for genetic assessment relatives of people with hemophilia or potential carriers of hemophilia, the WFH recommends the inclusion • Genetic testing is generally sought in all affected cases of a detailed family pedigree to support the genetic (probands) and “at-risk” female relatives within the family. testing referral. CB • Ideally, the disease-causing variant should first be identified in the proband or the obligate carrier. All other potential RECOMMENDATION 4.1.5: carriers may subsequently be screened for this variant to • For individuals with suspected hemophilia and potential confirm or exclude the carrier status. carriers of hemophilia, the WFH strongly recommends • If neither the proband nor the obligate carrier are available that phenotypic screening for FVIII or FIX levels, von for testing, the genetic assessment may still be performed Willebrand factor (VWF) antigen, and VWF activity in potential carriers; however, when a disease-causing testing be performed prior to referral for genetic testing. variant is not detected, it should be clearly mentioned in CB the report that failure to detect genetic variants with the existing techniques does not exclude the carrier status. RECOMMENDATION 4.1.6: • Carriers of hemophilia exhibit a wide range of factor levels, • For people with hemophilia, obligate carriers of with approximately 30% having levels <40 IU/dL.8 Women hemophilia, “at-risk” female relatives, or individuals and girls with low or borderline levels can experience a with low coagulation factor levels, the WFH strongly range of bleeding symptoms, usually consistent with mild recommends detailed genetic counselling prior to hemophilia, but hemarthrosis and more severe bleeding offering genetic testing. symptoms can occur.9,10 • REMARK: Genetic counselling should include a • Besides the heterozygosity for the disease-causing variant, discussion of the experimental limits of the molecular low factor levels in carriers of hemophilia may be attributed results according to the availability of practical to other epigenetic factors such as X-chromosome approaches. inactivation (XCI)11,12 or the ABO blood group system.13 • REMARK: Genetic counselling should include a • Pregnant women who are confirmed carriers of an F8 or F9 discussion of the possibility of incidental findings in variant may be offered non-invasive testing to determine genes other than F8 or F9, if the methodology used the sex of the fetus they are carrying in order to inform by the investigating laboratory (e.g., next generation subsequent options for prenatal diagnosis in a male fetus. sequencing [NGS]) may detect such genetic variations. This is achieved through analysis of cell-free fetal DNA • REMARK: Genetic counselling should be performed in the maternal plasma.14-16 by a genetic counsellor when available. If no genetic • Prenatal diagnosis may be offered to all confirmed carriers counsellor is available, a medical professional with of an F8 or F9 variant who are carrying a male fetus in Chapter 4: Genetic Assessment 57 early pregnancy by chorionic villus sampling or in late RECOMMENDATION 4.2.1: pregnancy by late-gestation amniocentesis, in order to • For people with suspected or established hemophilia guide the management of the delivery or to terminate undergoing genetic testing, the WFH recommends that the pregnancy in case of an affected fetus.17-20 Genetic the index case (pro-band) be genotyped to identify the counselling should include a discussion of the risk of the underlying genetic variant. CB PND procedure to the pregnancy. • Pre-implantation genetic diagnosis may be offered to RECOMMENDATION 4.2.2: confirmed carriers of an F8 or F9 variant in order to select • For obligate carriers of hemophilia and “at-risk” female an embryo that will not result in the birth of a male with relatives of the affected proband or potential carrier of hemophilia.21,22 hemophilia, the WFH recommends genetic counselling • It is important to be aware of and follow the relevant about their risk of being a carrier. CB laws governing genetic counselling and pre-implantation genetic diagnosis in the country where the services are RECOMMENDATION 4.2.3: being provided. • For all obligate carriers of hemophilia and “at-risk” • Among all the genetic risk factors, the nature of disease- female relatives of people with hemophilia or potential causing variants in both F8 and F9 has been found to be carriers of hemophilia, the WFH
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