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Next‐generation sequencing for the diagnosis of MYH9 ‐RD: Predicting pathogenic variants
Author(s) -
Bury Loredana,
Megy Karyn,
Stephens Jonathan C.,
Grassi Luigi,
Greene Daniel,
Gleadall Nick,
Althaus Karina,
Allsup David,
Bariana Tadbir K.,
Bonduel Mariana,
Butta Nora V.,
Collins Peter,
Curry Nicola,
Deevi Sri V. V.,
Downes Kate,
Duarte Daniel,
Elliott Kim,
Falcinelli Emanuela,
Furie Bruce,
Keeling David,
Lambert Michele P.,
Linger Rachel,
Mangles Sarah,
Mapeta Rutendo,
Millar Carolyn M.,
Penkett Christopher,
Perry David J.,
Stirrups Kathleen E.,
Turro Ernest,
Westbury Sarah K.,
Wu John,
BioResource NIHR,
Gomez Keith,
Freson Kathleen,
Ouwehand Willem H.,
Gresele Paolo,
Simeoni Ilenia
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23927
Subject(s) - bleeding diathesis , biology , phenotype , medicine , platelet , immunology , genetics , gene
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.