National strategic advocacy to manage patients with inherited bleeding disorders in low and lower-middle income countries.

INTRODUCTION: Inherited bleeding disorders (IBDs) including hemophilia, von Willebrand disease, platelet disorders, mucocutaneous bleeding disorders and coagulation factor deficiencies are rarely found and under-recognized in low and lower-middle-income countries. Some patients succumbed to serious bleeding without diagnosis and treatment during childhood. AREA COVERED: Diagnosis, management, and prevention should be integrated into the existing health care system. Although some countries have not implemented appropriate health care infrastructure, an initiative plan should be set up by cooperation of experienced experts and health care providers. Identification of patients with IBDs should be started in the antenatal setting to search for females at risk of carrier state. The investigations include bleeding assessment, mixing venous clotting time, coagulogram, coagulation factor assay and mutation detection. Genotypic analysis is helpful for confirming the definite diagnosis, carrier detection as well as prenatal diagnosis for females at risk of bearing an offspring with severe bleeding manifestations. Management involves replacement therapy ranging from blood component to virus-inactivated factor concentrate. Appropriate research is an essential backbone for improving patients' care. EXPERT OPINION: Effective national strategic advocacy to manage patients with IBDs requires intensive collaboration among policy makers, health care providers, patients, and family members.

Bombardier Blood (2020): Un documental más allá de la enfermedad / Bombardier Blood (2020): A Documentary beyond the Illness

Si bien la hemofilia era conocida como una enfermedad que perturbaba solo a las familias reales de Europa, actualmente afecta a uno de cada 5.000 y a uno de cada 30.000 varones recién nacidos vivos tanto para la de Tipo A como B, respectivamente. La hemofilia es un trastorno de la coagulación sanguínea que afecta principalmente a varones por su carácter de herencia recesiva ligada al X, siendo su manifestación principal las hemorragias que pueden llegar a ser mortales si no son tratadas correctamente. En Bombardier Blood (2020) de Patrick James Lynch, un documental enfocado al recorrido de Chris Bombardier, una persona hemofílica cuyo sueño es escalar las siete cumbres más altas del mundo, incluyendo en su paso el monte Everest en el Himalaya. El documental además de destacar los aspectos médicos sobre esta enfermedad hace ver los diferentes estilos de vida de acuerdo a su localización, las normativas y sistemas de salud que los rige y como esto incide en el diagnóstico, seguimiento y tratamiento. (AU)

While hemophilia was considered a disease that disturbed only the royal families of Europe, it currently affects one in 5.000 and one in 30.000 live newborn males for both Type A and B, respectively. Hemophilia is a blood clotting disorder that mainly affects men due to its character of recessive inheritance linked to X, its main manifestation hemorrhaging that can become fatal if they are not treated correctly. Bombardier Blood (2020) by Patrick James Lynch is a documentary focused on the journey of Chris Bombardier, a hemophilic person whose dream is to climb the seven highest summits in the world, including Mount Everest in the Himalayas. The documentary, in addition to highlighting the medical aspects of this disease, shows the different lifestyles according to their location, the regulations and health systems that govern them, and how these affect diagnosis, monitoring, and treatment. (AU)

Preoperative diagnosis and management of inherited bleeding disorders in female adolescents and adults.

Although inherited bleeding disorders (IBDs) affect both females and males, this review of the preoperative diagnosis and management of IBDs focuses on genetic and gynecologic screening, diagnosis and management of affected and carrier females. A PubMed literature search was conducted, and the peer-reviewed literature on IBDs was evaluated and summarized. Best-practice considerations for screening, diagnosis and management of IBDs in female adolescents and adults, with GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) evidence level and ranking of recommendation strength, are presented. Health care providers need to increase their recognition of and support for female adolescents and adults with IBDs. Improved access to counselling, screening, testing and hemostatic management is also required. Patients should be educated and encouraged to report abnormal bleeding symptoms to their health care provider when they have a concern. It is hoped that this review of preoperative IBD diagnosis and management will enhance access to women-centred care to increase patients' understanding of IBDs and decrease their risk of IBD-related morbidity and mortality.

Prevalence of hemorrhagic ovarian cysts in patients with rare inherited bleeding disorders.

BACKGROUND: In comparison with the general population, women with bleeding disorders are more prone to develop obstetrical and gynecological problems. However, no comprehensive evaluation has investigated the prevalence of hemorrhagic ovarian cysts (HOCs) in rare bleeding disorders (RBDs). In this study, we sought to determine the prevalence of HOCs in a large cohort of Iranian patients with RBDs. METHODS: A total of 210 symptomatic patients suspected of HOCs with RBD were included. The median age of the study population was 24 years. Patients were diagnosed with fibrinogen disorders (n = 7, 3%), factor (F) II (n = 4, 2%), FV (n = 28, 13%), FVII (n = 4, 2%), FX (n = 6, 3%), FXIII (n = 122, 58%), combined FV and FVIII (n = 8, 4%), Glanzmann's thrombasthenia (n = 10, 5%), and von Willebrand disease (VWD) type 3 (n = 21, 10%). RESULTS: Following further clinical and ultrasound examinations of these 210 patients, 68 (32.4%) were confirmed with a diagnosis of HOCs. Of which, FXIII deficiency with 46 cases (67.6%), followed by VWD type 3 (6 cases, 8.8%) showed the highest number. Other coagulation defects associated with HOCs were including fibrinogen deficiency (n = 2, 3%), FII (n = 2, 3%), FV (n = 4, 6%), FVII (n = 2, 3%), FX (n = 1, 1.5%), combined FV and FVIII (n = 2, 3%), and Glanzmann's thrombasthenia (n = 3, 4.5%). CONCLUSION: This study found a high prevalence of HOCs in patients with RBDs, indicating the importance of early diagnosis and optimal management of obstetric and gynecological complications in these patients.

Molecular basis of rare congenital bleeding disorders.

Rare bleeding disorders (RBDs), including factor (F) I, FII, FV, FVII, combined FV and FVIII (CF5F8), FXI, FXIII and vitamin-K dependent coagulation factors (VKCF) deficiencies, are a heterogeneous group of hemorrhagic disorder with a variable bleeding tendency. RBDs are due to mutation in underlying coagulation factors genes, except for CF5F8 and VKCF deficiencies. FVII deficiency is the most common RBD with >330 variants in the F7 gene, while only 63 variants have been identified in the F2 gene. Most detected variants in the affected genes are missense (>50% of all RBDs), while large deletions are the rarest, having been reported in FVII, FX, FXI and FXIII deficiencies. Most were located in the catalytic and activated domains of FXI, FX, FXIII and prothrombin deficiencies. Understanding the proper molecular basis of RBDs not only can help achieve a timely and cost-effective diagnosis, but also can help to phenotype properties of the disorders.

[Partial research progress of GGCX pathogenic variation associated phenotypes].

γ-glutamyl carboxylase (GGCX), also known as vitamin K-dependent glutamyl carboxylase, catalyzes the posttranslational modification of specific glutamate residues in vitamin K-dependent proteins (VKDPs), and participates multiple biological functions including blood coagulation, bone metabolism, vascular calcification, and cell proliferation. It has been reported originally that GGCX pathogenic variation causes blood coagulation deficiency, which is called as vitamin K-dependent coagulation factor deficiency 1 (VKCFD1). Recently, it has been found that GGCX gene variation results in multiple clinical phenotypes, including dermatological, ophthalmological, skeletal or cardiac abnormalities. Among them, dermatological phenotype is the most common, which is known as pseudoxanthoma elasticum-like syndrome. This paper has reviewed the GGCX pathogenic variation associated phenotypes, in order to increase the recognition of GGCX-related genetic diseases and to help its diagnosis and treatment.

JTH in Clinic - Obstetric bleeding: VWD and other inherited bleeding disorders.

Individuals with inherited bleeding disorders (IBDs) have higher bleeding risk during pregnancy, childbirth, and the postpartum period. Clinical management requires recognition of the IBD as high risk for postpartum hemorrhage and a personalized multidisciplinary approach that includes the patient in decision making. When the fetus is known or at risk to inherit a bleeding disorder, fetal and neonatal bleeding risk also need to be considered. In pregnant IBD patients, it is common for providers to need to make decisions in the absence of high level of certainty evidence. We here present the case of a pregnant von Willebrand disease patient that reached multiple decision points where there is currently clinical ambiguity due to a lack of high level of certainty evidence. For each stage of her care, from diagnosis to the postpartum period, we discuss current literature and describe our approach. This is followed by a brief overview of considerations in other IBDs and pregnancy.

The Role of GRP and MGP in the Development of Non-Hemorrhagic VKCFD1 Phenotypes.

Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in γ-Glutamyl carboxylase (GGCX) gene. The GGCX enzyme catalyzes the γ-carboxylation of 15 different vitamin K dependent (VKD) proteins, which have function in blood coagulation, calcification, and cell signaling. Therefore, in addition to bleedings, some VKCFD1 patients develop diverse non-hemorrhagic phenotypes such as skin hyper-laxity, skeletal dysmorphologies, and/or cardiac defects. Recent studies showed that GGCX mutations differentially effect γ-carboxylation of VKD proteins, where clotting factors are sufficiently γ-carboxylated, but not certain non-hemostatic VKD proteins. This could be one reason for the development of diverse phenotypes. The major manifestation of non-hemorrhagic phenotypes in VKCFD1 patients are mineralization defects. Therefore, the mechanism of regulation of calcification by specific VKD proteins as matrix Gla protein (MGP) and Gla-rich protein (GRP) in physiological and pathological conditions is of high interest. This will also help to understand the patho-mechanism of VKCFD1 phenotypes and to deduce new treatment strategies. In the present review article, we have summarized the recent findings on the function of GRP and MGP and how these proteins influence the development of non-hemorrhagic phenotypes in VKCFD1 patients.

Genetic and Bioinformatic Strategies to Improve Diagnosis in Three Inherited Bleeding Disorders in Bogotá, Colombia.

Inherited bleeding disorders (IBDs) are the most frequent congenital diseases in the Colombian population; three of them are hemophilia A (HA), hemophilia B (HB), and von Willebrand Disease (VWD). Currently, diagnosis relies on multiple clinical laboratory assays to assign a phenotype. Due to the lack of accessibility to these tests, patients can receive an incomplete diagnosis. In these cases, genetic studies reinforce the clinical diagnosis. The present study characterized the molecular genetic basis of 11 HA, three HB, and five VWD patients by sequencing the F8, F9, or the VWF gene. Twelve variations were found in HA patients, four in HB patients, and 19 in WVD patients. From these variations a total of 25 novel variations were found. Disease-causing variations were used as positive controls for validation of the high-resolution melting (HRM) variant-scanning technique. This approach is a low-cost genetic diagnostic method proposed to be incorporated in developing countries. For the data analysis, we developed an accessible open-source code in Python that improves HRM data analysis with better sensitivity of 95% and without bias when using different HRM equipment and software. Analysis of amplicons with a length greater than 300 bp can be performed by implementing an analysis by denaturation domains.

Main Factors Predicting Nonresponders to Autologous Cell Therapy for Critical Limb Ischemia in Patients With Diabetic Foot.

Autologous cell therapy (ACT) is a new treatment for patients with no-option critical limb ischemia (NO-CLI). We evaluated the factors involved in the nonresponse to ACT in patients with CLI and diabetic foot. Diabetic patients (n = 72) with NO-CLI treated using ACT in our foot clinic over a period of 8 years were divided into responders (n = 57) and nonresponders (n = 15). Nonresponder was defined as an insufficient increase in transcutaneous oxygen pressure by <5 mm Hg, 3 months after ACT. Patient demographics, diabetes duration and treatment, and comorbidities as well as a cellular response to ACT, limb-related factors, and the presence of inherited thrombotic disorders were compared between the 2 groups. The main independent predictors for an impaired response to ACT were heterozygote Leiden mutation (OR 10.5; 95% CI, 1.72-4) and homozygote methylenetetrahydrofolate reductase (MTHFR 677) mutation (OR 3.36; 95% CI, 1.0-14.3) in stepwise logistic regression. Univariate analysis showed that lower mean protein C levels (P = .041) were present in nonresponders compared with responders. In conclusion, the significant predictors of an impaired response to ACT in diabetic patients with NO-CLI were inherited thrombotic disorders.

[Development of a cell-based diagnostic system for vitamin K-dependent coagulation factor deficiency 1].

OBJECTIVE: To develop a cell-based system for the diagnosis of vitamin K-dependent coagulation factor deficiency 1 (VKCFD1). METHODS: In HEK293 cells stably expressing the reporter gene FIX-Gla-PC, the gamma-glutamyl carboxylase (GGCX) gene was knocked out by using CRISPR/Cas9 technology. Enzyme-linked immunosorbent assay (ELISA), DNA sequencing and Western blotting were used to identify the GGCX gene knockout cells. A quickchange point variant method was used to construct the GGCX variant. ELISA was used to assess the influence of GGCX variant on the activity of reporter gene. RESULTS: Two monoclonal cell lines with no reporter activity by ELISA was identified. Edition and knockout of the GGCX gene was confirmed by DNA sequencing and Western blotting. The activity of the reporter gene was recovered by transfection of the wild-type GGCX gene. Thereby two monoclonal cells with GGCX knockout were obtained. By comparing the wild-type and pathogenic GGCX variants, the reporter activity was decreased in the pathogenic variants significantly. CONCLUSION: A cell-based system for the detection of GGCX activity was successfully developed, which can be used for the diagnosis of VKCFD1 caused by GGCX variants.

Osteoporosis transitoria de cadera familiar ligada al factor V de Leiden / Transient familial factor V Leiden-linked hip osteoporosis

INTRODUCCIÓN: La osteoporosis transitoria de cadera (OTC) es una enfermedad poco frecuente y de patogenia desconocida que ha sido considerada tradicionalmente una fase precoz y reversible de la necrosis avascular (NA). La trombofilia o la hipofibrinólisis familiar se considera un factor de riesgo para el desarrollo de NA y OTC. Dentro de los trastornos heredados de hipercoagulabilidad, el factor V de Leiden es uno de los más prevalentes. Casos clínicos: Estudio tipo serie de casos. Se describen el desarrollo y la evolución de 3 casos de OTC en 3 hermanos (2 varones y una mujer) con edades comprendidas entre los 40 y 43 años de forma consecutiva. El estudio clínico y de imagen con resonancia magnética nuclear (RM) confirmó el diagnóstico de OTC y descartó la presencia de NA. La mutación G1691A para el factor V de Leiden fue positiva en todos los casos. La evolución clínica y radiológica fue favorable, con curación sin secuelas y desaparición del edema óseo en la RM de control a los 6 meses en todos los casos. DISCUSIÓN: Los resultados del presente estudio apoyan la etiología isquémica y establecen a la OTC como una fase precoz y reversible de la NA de cadera. El factor V de Leiden promueve un estado de hipercoagulabilidad e hipofibrinólisis que favorece el desarrollo de la OTC por causa isquémica. CONCLUSIONES: El presente estudio desarrolla la primera descripción familiar de la OTC ligada al factor V de Leiden

INTRODUCTION: Transient osteoporosis of the hip (THO) is a rare disease of unknown pathogenesis that has traditionally been considered an early and reversible stage of avascular necrosis (AN). Thrombophilia or familial hypofibrinolysis is considered a risk factor for the development of AN and THO. Factor V Leiden is one of the most common hereditary hypercoagulability disorders. Clinical cases: Case series study. The development and course of 3 THO cases in 3 siblings (two males and one female) aged between 40 and 43 years are described consecutively. Clinical and nuclear magnetic resonance imaging (MRI) studies confirmed the diagnosis of THO and ruled out the presence of AN. The G1691A mutation of factor V Leiden was positive in all cases. The clinical and radiological outcome was favourable, with healing without sequelae and disappearance of bone oedema on control MRI at 6 months in all cases. DISCUSSION: The results of this study support the ischaemic aetiology and establish HTO as an early and reversable stage of hip AN. Factor V Leiden causes a state of hypercoagulability and hypofibrinolysis that encourages the development of THO due to ischaemic causes. CONCLUSIONS: This study outlines the first familiar description of factor V Leiden-linked THO

[Inherited bleeding disorders in adolescents with excessive menstrual bleeding. Should we evaluate the fibrinolytic pathway?] / Trastornos hereditarios de la coagulación en adolescentes con sangrado menstrual excesivo, ¿debemos evaluar la vía fibrinolítica?

INTRODUCTION: Heavy Menstrual Bleeding (EMB) is a frequent problem in adolescence. The prevalence of inherited bleeding disorders (IBD) as a cause of EMB is not well established and the involvement of fibri nolytic pathway defects has been poorly explored. OBJECTIVE: To determine the prevalence of IBD and fibrinolysis defects in adolescents with EMBs. PATIENTS AND METHOD: 93 adolescents (11 to 18 years old) were included. Personal and family history of bleeding were obtained through a standard ized questionnaire. The following lab tests were performed: prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor quantification, and platelet count and function. Those patients who were not diagnosed with IBD were further evaluated with clot lysis time assay. RESULTS: 41 patients (44%) were diagnosed as IBD (Von Willebrand disease n = 28, platelet func tion defects n=8, mild hemophilia n = 5. Decreased clot lysis time was found in 31 patients. 54% of patients diagnosed with IBD had EMB as the first hemorrhagic manifestation. CONCLUSION: These results support the need to evaluate the coagulation process, including the fibrinolytic pathway in the study of adolescents with EMB.

The impact of foetal restrictions on mode of delivery in women with inherited bleeding disorders.

OBJECTIVES: Management of pregnancy in women with congenital bleeding disorders (CBD) is challenging and requires understanding of risks conferred to both the mother and the foetus. Some elements of labour management are considered to increase the risk of neonatal bleeding and are not recommended for neonates at risk of a significant bleeding disorder. The impact of these restrictions on obstetric outcomes in women with CBD is unknown. METHODS: We retrospectively reviewed obstetric outcomes in a large cohort of women with CBD attending a specialised obstetric/haematology antenatal clinic over a 6-year period. RESULTS: Ninety-four pregnancies in 76 women with a wide variety of CBDs were assessed. Foetal precautions were recommended in the majority of cases (88%). Twenty (21.2%) were delivered by elective Caesarean section (CS), predominantly for obstetric indications. Of the 63 women who laboured with foetal precautions in place, 6 (10%) had a CS that was performed because of these precautions. There was no neonatal bleeding but primary postpartum haemorrhage (PPH) occurred in 12.2% of women. CONCLUSIONS: These data show that foetal precautions in labour recommended for women with CBDs will influence mode of delivery in approximately 10% of cases. This is important information for counselling these women about labour and delivery.

Strengths and limitations of high-throughput sequencing for the diagnosis of inherited bleeding and platelet disorders.

Inherited bleeding and platelet disorders (BPD) are highly heterogeneous and their diagnosis involves a combination of clinical investigations, laboratory tests, and genetic screening. This review will outline some of the challenges that geneticists and experts in clinical hemostasis face when implementing high-throughput sequencing (HTS) for patient care. We will provide an overview of the strengths and limitations of the different HTS techniques that can be used to diagnose BPD. An HTS test is cost-efficient and expected to increase the diagnostic rate with a possibility to detect unexpected diagnoses and decrease the turnaround time to diagnose patients. On the other hand, technical shortcomings, variant interpretation difficulties, and ethical issues related to HTS for BPD will also be documented. Delivering a genetic diagnosis to patients is highly desirable to improve clinical management and allow family counseling, but making incorrect assumptions about variants and providing insufficient information to patients before initiating the test could be harmful. Data-sharing and improved HTS guidelines are essential to limit these major drawbacks of HTS.

Trastornos hereditarios de la coagulación en adolescentes con sangrado menstrual excesivo, ¿debemos evaluar la vía fibrinolítica? / Inherited bleeding disorders in adolescents with excessive menstrual bleeding: should we evaluate the fibrinolytic pathway?

Resumen: Introducción: El Sangrado Menstrual Excesivo (SME) es un problema frecuente en la adolescencia. La prevalencia de trastornos hereditarios de la coagulación (THC) como causa del SME no está bien establecida y la participación de defectos de la vía fibrinolítica ha sido poco explorada. Objetivo: Determinar la prevalencia de THC y defectos de la fibrinólisis en adolescentes con SME. Pacientes y Método: Se incluyeron 93 adolescentes, edad 11 a 18 años. Los antecedentes personales y familiares de sangra do se obtuvieron con un cuestionario estandarizado. Se controló exámenes: tiempo de protrom- bina (TP), tiempo de tromboplastina parcial activada (TTPa), estudio del factor Von Willebrand, recuento y función plaquetaria. Los pacientes que no fueron diagnosticados como THC, se evaluaron adicionalmente con el tiempo de lisis del coágulo. Resultados: 41 pacientes (44%) fueron diagnos ticados como THC: Enfermedad de Von Willebrand n = 28, defectos de la función plaquetaria n = 8, hemofilia leve n = 5. Se confirmó disminución del tiempo de lisis del coágulo en 31 pacientes. El 54% de pacientes diagnosticado como THC, tuvo SME como la primera manifestación hemorrágica. Conclusión: Estos resultados apoyan la necesidad de evaluación de la coagulación, incluyendo la vía fibrinolítica, en el estudio de adolescentes con SME.

Abstract: Introduction: Heavy Menstrual Bleeding (EMB) is a frequent problem in adolescence. The prevalence of inherited bleeding disorders (IBD) as a cause of EMB is not well established and the involvement of fibri nolytic pathway defects has been poorly explored. Objective: To determine the prevalence of IBD and fibrinolysis defects in adolescents with EMBs. Patients and Method: 93 adolescents (11 to 18 years old) were included. Personal and family history of bleeding were obtained through a standard ized questionnaire. The following lab tests were performed: prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor quantification, and platelet count and function. Those patients who were not diagnosed with IBD were further evaluated with clot lysis time assay. Results: 41 patients (44%) were diagnosed as IBD (Von Willebrand disease n = 28, platelet func tion defects n=8, mild hemophilia n = 5. Decreased clot lysis time was found in 31 patients. 54% of patients diagnosed with IBD had EMB as the first hemorrhagic manifestation. Conclusion: These results support the need to evaluate the coagulation process, including the fibrinolytic pathway in the study of adolescents with EMB.

Heavy menstrual bleeding in women with inherited bleeding disorders.

Heavy menstrual bleeding (HMB) is the commonest bleeding symptom among women with inherited bleeding disorders (IBD). Since HMB starts at the very onset of menarche and continues throughout the reproductive life, the health related quality of life of these women is affected and they are at an increased risk of developing iron-deficiency anemia. Because of the entrenched stigma and taboos, women and girls are often reluctant to discuss the problem of HMB within their families and do not seek medical advice. Increased awareness and multidisciplinary management approach for the management of these women are essential in ensuring an optimal outcome. It is important to take a careful history and undertake a thorough gynecological assessment to exclude other underlying/concomitant causes of HMB. Iron supplementation is essential. Strategies for decreasing menstrual blood flow are similar to those used for HMB in general with the addition of desmopressin and replacement therapy and the exclusion of non-steroidal anti-inflammatory drugs. Tranexamic acid and/or hormonal intervention are usually recommended as first-line therapy. Treatment choice should be individualized taking into account whether the woman wishes to preserve her fertility, if she requires contraception, the type of IBD, the severity of bleeding, and her social and religious background as well as acceptability and availability of the treatment options.

Genetic screening of children with suspected inherited bleeding disorders.

INTRODUCTION: Genetic screening using high-throughput DNA sequencing has become a tool in diagnosing patients with suspected inherited bleeding disorders (IBD). However, its usefulness and diagnostic efficacy in children is unclear. AIM: To evaluate the diagnostic efficacy of genetic screening for IBD in children and downstream further testing. METHODS: After informed consent, children (<18 years) with suspected IBD underwent genetic screening with 94 selected genes. RESULTS: A total of 68 heterozygous class 3-5 variants were detected in 30 children, 2.3 variants per patient. Directed specific functional testing was performed after genetic screening in a subset of patients. Adhering to the ACMG guidelines, the results of functional testing together with family history and previous publications classified three variants as likely disease causing (class 4) and two variants as disease causing (class 5), all in children with thrombocytopenia. The overall diagnostic rate was 16.7% (5/30). Children with thrombocytopenia had a significantly higher rate of significant genetic findings, 5/9 (55.6%) vs. 0/21 (0%; P = .0009). CONCLUSION: We conclude that performing genetic screening in children is an effective tool especially for children with inherited thrombocytopenia and has the possibility to diagnose platelet disorders adequately early in life. Children with bleeding diathesis, normal coagulation work-up and without thrombocytopenia are unlikely to be diagnosed by genetic screening. Ethical issues such as incidental findings, variants associated with cancer and the interpretation of the genetic results into clinical practice remain problematic.