Next-generation sequencing for the diagnosis of MYH9-RD: predicting pathogenic variants.

Bury L1, Megy K2,3, Stephens JC2,3, Grassi L2,3, Greene D2,3,4, Gleadall N2,3, Althaus K5,6, Allsup D7, Bariana TK2,3,8, Bonduel M9, Butta NV10, Collins P11, Curry N12, Deevi SV2,3, Downes K2,3, Duarte D2,3, Elliott K13, Falcinelli E1, Furie B14, Keeling D15, Lambert MP16,17, Linger R2,3, Mangles S18, Mapeta R2,3, Millar CM19,20, Penkett C2,3, Perry DJ4, Stirrups KE2,3, Turro E2,3,21, Westbury SK22, Wu J23, BioResource N24, Gomez K7, Freson K25, Ouwehand WH2,3,26,27, Gresele P1, Simeoni I2,3.

Author information

1: Department of Internal Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy.
2: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
3: NIHR BioResource - Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, UK.
4: Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
5: Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.
6: Center for Clinical Transfusion Medicine Tuebingen, Tuebingen, Germany.
7: Hull York Medical School, York, UK.
8: The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, UK.
9: Hematology/Oncology Department. Hospital de Pediatría "Prof. Dr. Juan P. Garrahan", Buenos Aires, Argentina.
10: Servicio de Hematología y Hemoterapia Hospital Universitario La Paz-IDIPaz, Madrid, Spain.
11: Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, UK.
12: Oxford Radcliffe Hospitals NHS Trust.
13: Oxford Haemophilia & Thrombosis Centre, Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford and the NIHR BRC, Blood Theme, Oxford Centre for Haematology, Oxford, UK.
14: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
15: Churchill Hospital, Oxford University Hospitals, UK.
16: Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
17: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA.
18: Basingstoke and Hampshire NHS Foundation Trust.
19: Hampshire Hospital NHS Foundation Trust, UK.
20: Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, UK.
21: Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, UK.
22: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
23: B.C. Children's Hospital, Vancouver, Canada.
24: NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
25: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
26: NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
27: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

Abstract

The heterogeneous manifestations of the MYH9-related disorder (MYH9-RD), characterized by macrothrombocytopenia, Döhle-like inclusion bodies in leukocytes, bleeding of various severity with in some cases ear, eye, kidney and liver involvement make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analysed the genetic variations in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE-BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental to diagnose 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9-RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9-RD should always be suspected. A HTS-based strategy is a reliable method to reach a conclusive diagnosis of MYH9-RD in clinical practice. This article is protected by copyright. All rights reserved.