TY - JOUR
T1 - Next-generation sequencing for the diagnosis of MYH9-RD
T2 - Predicting pathogenic variants
AU - Bury, Loredana
AU - Megy, Karyn
AU - Stephens, Jonathan C.
AU - Grassi, Luigi
AU - Greene, Daniel
AU - Gleadall, Nick
AU - Althaus, Karina
AU - Allsup, David
AU - Bariana, Tadbir K.
AU - Bonduel, Mariana
AU - Butta, Nora V.
AU - Collins, Peter
AU - Curry, Nicola
AU - Deevi, Sri V.V.
AU - Downes, Kate
AU - Duarte, Daniel
AU - Elliott, Kim
AU - Falcinelli, Emanuela
AU - Furie, Bruce
AU - Keeling, David
AU - Lambert, Michele P.
AU - Linger, Rachel
AU - Mangles, Sarah
AU - Mapeta, Rutendo
AU - Millar, Carolyn M.
AU - Penkett, Christopher
AU - Perry, David J.
AU - Stirrups, Kathleen E.
AU - Turro, Ernest
AU - Westbury, Sarah K.
AU - Wu, John
AU - BioResource, N. I.H.R.
AU - Gomez, Keith
AU - Freson, Kathleen
AU - Ouwehand, Willem H.
AU - Gresele, Paolo
AU - Simeoni, Ilenia
N1 - Publisher Copyright:
© 2019 The Authors. Human Mutation published by Wiley Periodicals, Inc.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
KW - ACMG guidelines
KW - MYH9-related disorders
KW - clinical diagnosis
KW - genomics
KW - high throughput sequencing
KW - variant classification
UR - https://www.scopus.com/pages/publications/85074111752
U2 - 10.1002/humu.23927
DO - 10.1002/humu.23927
M3 - Article
C2 - 31562665
AN - SCOPUS:85074111752
SN - 1059-7794
VL - 41
SP - 277
EP - 290
JO - Human Mutation
JF - Human Mutation
IS - 1
ER -