Design and application of a 23‐gene panel by next‐generation sequencing for inherited coagulation bleeding disorders

Bastida, José María; Rey, Mónica del; Lozano, Marı́a Luisa; Sarasquete, María Eugenia; Benito, Rocí­o; Fontecha, M. E.; Fisac, Rosa; García-Frade, Luis Javier; Aguilar, Carlos; Martínez, María Paz; Pardal, Emilia; Aguilera, Carmen; Pérez, B.; Ramos, Rúben J.; Cardesa, M. R.; Martín‐Antorán, J.M.; Silvestre, L. A.; Cebeira, María José; Bermejo, Nuria; Riesco, Susana; Mendoza, M. C.; García‐Sanz, Ramón; González‐Díaz, Marcos; Hernández‐Rivas, Jesús María; González‐Porras, José Ramón

doi:10.1111/hae.12908

Cited by 47 publications

(62 citation statements)

References 41 publications

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“…Although proof-of-principle NGS has been reported for genotyping and discovery in patients with bleeding disorders, ,50 hemophilia A and B patients have been previously reported using NGS in approaches that cannot detect F8 inversions. [24][25][26] In the first 3000 MLOF patients reported here, the spectrum of types of F8 and F9 genetic variants we found was similar to that previously reported in hemophilia, including in a report of 829 US patients with hemophilia A or B. [1][2][3][4][5]12,[27][28][29][30] Surprisingly, despite a long history of genetic studies in hemophilia, we identified 273 previously unreported F8 and F9 DNA variants, significantly advancing our knowledge of the genetics of hemophilia.…”

Section: Discussionmentioning

confidence: 99%

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

et al. 2017

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• MLOF used an innovative approach to genotype 3000 hemophilia patients identifying likely causative variants in 98.4% of patients.• Hemophilia genotyping should include structural variation, F8 inversions (for hemophilia A), and consideration of gene-wide approaches.Hemophilia A and B are rare, X-linked bleeding disorders. My Life, Our Future (MLOF) is a collaborative project established to genotype and study hemophilia. Patients were enrolled at US hemophilia treatment centers (HTCs). Genotyping was performed centrally using nextgeneration sequencing (NGS) with an approach that detected common F8 gene inversions simultaneously with F8 and F9 gene sequencing followed by confirmation using standard genotyping methods. Sixty-nine HTCs enrolled the first 3000 patients in under 3 years.Clinically reportable DNA variants were detected in 98.1% (2357/2401) of hemophilia A and 99.3% (595/599) of hemophilia B patients. Of the 924 unique variants found, 285 were novel.Predicted gene-disrupting variants were common in severe disease; missense variants predominated in mild-moderate disease. Novel DNA variants accounted for ;30% of variants found and were detected continuously throughout the project, indicating that additional variation likely remains undiscovered. The NGS approach detected .1 reportable variants in 36 patients (10 females), a finding with potential clinical implications. NGS also detected incidental variants unlikely to cause disease, including 11 variants previously reported in hemophilia. Although these genes are thought to be conserved, our findings support caution in interpretation of new variants. In summary, MLOF has contributed significantly toward variant annotation in the F8 and F9 genes. In the near future, investigators will be able to access MLOF data and repository samples for research to advance our understanding of hemophilia.

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Section: Discussionmentioning

confidence: 99%

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

et al. 2017

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“…Advances in molecular genetic technologies using next‐generation sequencing allow a gene panel‐based approach to diagnosis of most of the common hereditary bleeding disorders. There is evolving and increasing use of this approach internationally . This indeed holds the potential to revolutionize the approach to diagnosis of hereditary bleeding disorders, particularly in developing countries .…”

Section: Principle 3: Genetic Diagnosis Of Hereditary Bleeding Disordmentioning

confidence: 99%

“…With current pathogen reduction methods, there has been no transmission of such infections for over three decades. Appropriately manufactured pdCFCs are therefore safe to use in PWH . However, recombinant CFCs (rCFCs) are often preferred because they do not contain any other human proteins and therefore considered to be safer.…”

Section: Principle 4 Regular Replacement Therapy With Clotting Factomentioning

confidence: 99%

“…Global production and supply is also much higher for rCFCs. Guidelines for selection of CFCs have been developed by WFH and should be carefully reviewed in the context of the healthcare system in each country. These guidelines should be incorporated into tender processes for procurement of CFCs.…”

Section: Principle 4 Regular Replacement Therapy With Clotting Factomentioning

confidence: 99%

“…There is evolving and increasing use of this approach internationally. 5,15 This indeed holds the potential to revolutionize the approach to diagnosis of hereditary bleeding disorders, particularly in developing countries. 3,16 It would be more feasible for technical and training reasons to set up central genetic diagnostic facilities at critical places in every country rather than the "traditional" haemostasis laboratories.…”

Section: Recommendationmentioning

confidence: 99%

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Principles of haemophilia care: The Asia‐Pacific perspective

et al. 2018

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Optimal haemophilia care is best established and implemented through a well-coordinated plan guided by clearly defined principles and priorities. A document which enunciates those details is therefore important. A successful example of this approach is the definition of principles of haemophilia care (PHC) outlined by the European Association for Haemophilia and Associated Disorders (EAHAD) and also the World Federation of Hemophilia. A similar document applicable to the Asia-Pacific region must take into account not only the highly varied healthcare systems but also the tremendous socio-economic and cultural diversities which impact provision of such care. The Asia-Pacific Haemophilia Working Group (APHWG), representing the countries in this region, has prepared this perspective of the PHC. While endorsing the overall framework outlined by EAHAD, this APHWG document emphasizes regional priorities on education and training of healthcare personnel in the diagnosis and management of hereditary bleeding disorders. Central coordinating agencies with wide stakeholder input, networks of haemophilia treatment centres and national registries as well as robust processes for procurement and distribution of safe and effective clotting factor concentrates (CFCs), implementation of prophylaxis programmes and management of patients with inhibitors should also be developed. The implementation of these strategies should lead to establishment of good comprehensive care programmes. This document should also be an advocacy tool to lobby for improved care for people with haemophilia (PWH) in the region. We urge national healthcare policy makers to consider these principles and initiate strong and decisive action to reach these goals.

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Monogenic Causes of Apparently Idiopathic Perinatal Intracranial Hemorrhage

Hausman-Kedem

Malinger

Modai³

et al. 2021

Annals of Neurology

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Objective Perinatal intracranial hemorrhage (pICH) is a rare event that occurs during the fetal/neonatal period with potentially devastating neurological outcome. However, the etiology of pICH is frequently hard to depict. We investigated the role of rare genetic variations in unexplained cases of pICH. Methods We performed whole‐exome sequencing (WES) in fetuses and term neonates with otherwise unexplained pICH and their parents. Variant causality was determined according to the American College of Medical Genetics and Genomics (ACMG) criteria, consistency between suggested genes and phenotypes, and mode of inheritance. Results Twenty‐six probands (25 families) were included in the study (9 with a prenatal diagnosis and 17 with a postnatal diagnosis). Intraventricular hemorrhage (IVH) was the most common type of hemorrhage (n = 16, 62%), followed by subpial (n = 4, 15%), subdural (n = 4, 15%), and parenchymal (n = 2, 8%) hemorrhage. Causative/likely causative variants were found in 4 subjects from 3 of the 25 families (12%) involving genes related to the brain microenvironment (COL4A1, COL4A2, and TREX‐1). Additionally, potentially causative variants were detected in genes related to coagulation (GP1BA, F11, Von Willebrand factor [VWF], FGA, and F7; n = 4, 16%). A potential candidate gene for phenotypic expansion related to microtubular function (DNAH5) was identified in 1 case (4%). Fifty‐five percent of the variants were inherited from an asymptomatic parent. Overall, these findings showed a monogenic cause for pICH in 12% to 32% of the families. Interpretation Our findings reveal a clinically significant diagnostic yield of WES in apparently idiopathic pICH and support the use of WES in the evaluation of these cases. ANN NEUROL 2021;89:813–822

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Design and application of a 23‐gene panel by next‐generation sequencing for inherited coagulation bleeding disorders

Abstract: Our results demonstrate that this approach could be an accurate, reproducible and reliable tool in the rapid genetic diagnosis of IBCDs.

Cited by 47 publications

References 41 publications

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

Principles of haemophilia care: The Asia‐Pacific perspective

Monogenic Causes of Apparently Idiopathic Perinatal Intracranial Hemorrhage

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