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Next‐generation sequencing for the diagnosis of MYH9 ‐RD: Predicting pathogenic variants

Research output: Contribution to journalArticle

Loredana Bury, Karyn Megy, Jonathan C. Stephens, Luigi Grassi, Daniel Greene, Nick Gleadall, Karina Althaus, David Allsup, Tadbir K. Bariana, Mariana Bonduel, Nora V. Butta, Peter Collins, Nicola Curry, Sri V. V. Deevi, Kate Downes, Daniel Duarte, Kim Elliott, Emanuela Falcinelli, Bruce Furie, David Keeling & 18 more Michele P. Lambert, Rachel Linger, Sarah Mangles, Rutendo Mapeta, Carolyn M. Millar, Christopher Penkett, David J. Perry, Kathleen E. Stirrups, Ernest Turro, Sarah K. Westbury, John Wu, Nihr Bioresource, Keith Gomez, Kathleen Freson, Willem H. Ouwehand, Paolo Gresele, Ilenia Simeoni, Catherine Williamson

Original languageEnglish
Pages (from-to)277-290
Number of pages14
JournalHuman Mutation
Issue number1
Early online date15 Oct 2019
Publication statusPublished - 1 Jan 2020


King's Authors


The heterogeneous manifestations of MYH9 ‐related disorder (MYH9‐RD), characterized by macrothrombocytopenia, Döhle‐like inclusion bodies in leukocytes, bleeding of variable 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 analyzed the genetic variants 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 of the 50 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 in diagnosing 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 considered. A HTS‐based strategy is a reliable method to reach a conclusive diagnosis of MYH9 ‐RD in clinical practice.

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