Sunday, October 6, 2019

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

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

 2019 Sep 28. doi: 10.1002/humu.23927. [Epub ahead of print]

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

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.

KEYWORDS:

ACMG Guidelines; MYH9-related disorders; clinical diagnosis; genomics; high throughput next generation sequencing; variant classification

PMID:
 
31562665
 
DOI:
 
10.1002/humu.23927

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