Next-generation sequencing for the diagnosis of MYH9-RD: Predicting pathogenic variants.
Adolescent
Adult
Aged
Alleles
Child
Child, Preschool
Chromosome Mapping
Evolution, Molecular
Female
Fluorescent Antibody Technique
Gene Expression
Genetic Association Studies
/ methods
Genetic Predisposition to Disease
Genetic Variation
Genotype
High-Throughput Nucleotide Sequencing
/ methods
Humans
Infant
Male
Middle Aged
Mutation
Myosin Heavy Chains
/ genetics
Phenotype
Young Adult
ACMG guidelines
MYH9-related disorders
clinical diagnosis
genomics
high throughput sequencing
variant classification
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
19
04
2019
revised:
19
09
2019
accepted:
25
09
2019
pubmed:
29
9
2019
medline:
20
5
2021
entrez:
29
9
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31562665
doi: 10.1002/humu.23927
pmc: PMC6972977
doi:
Substances chimiques
MYH9 protein, human
0
Myosin Heavy Chains
EC 3.6.4.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
277-290Subventions
Organisme : NHS Blood and Transplant
ID : RBAG/142
Pays : International
Organisme : Department of Health
ID : RG65966
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/J011711/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : RBAG/342
Pays : United Kingdom
Organisme : British Heart Foundation
ID : 208
Pays : United Kingdom
Organisme : MRC
ID : 295
Pays : International
Organisme : European Commission
ID : RBAG/344
Pays : International
Organisme : British Heart Foundation
ID : RBAG/245
Pays : United Kingdom
Organisme : British Heart Foundation
ID : 226
Pays : United Kingdom
Organisme : MRC
ID : RBAG/285
Pays : International
Organisme : Department of Health
ID : RBAG/181
Pays : United Kingdom
Informations de copyright
© 2019 The Authors. Human Mutation published by Wiley Periodicals, Inc.
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