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

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

doi:10.1002/humu.23927

Abstract

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.

Highlights

Nonmuscle myosin heavy chain 9 related disorder (MYH9‐RD) is a rare autosomal‐dominant syndrome characterized by large/giant platelets and thrombocytopenia associated with the presence of Döhle‐like inclusion bodies in neutrophils (Kunishima et al, 2003)
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 found that 39% of the patients with severe thrombocytopenia have a variant affecting exons in the head domain (HD) and 61% of the individuals had a variant in the coiled coil domain instead

Summary

| INTRODUCTION

Nonmuscle myosin heavy chain 9 related disorder (MYH9‐RD) is a rare autosomal‐dominant syndrome characterized by large/giant platelets and thrombocytopenia associated with the presence of Döhle‐like inclusion bodies in neutrophils (Kunishima et al, 2003). The diagnosis of MYH9‐RD requires skilled laboratory investigations, including the correct assessment of the degree of thrombocytopenia, made difficult by the abnormal size of platelets, the identification of macrothrombocytes, and the determination of the presence of Döhle‐like inclusion bodies in neutrophils on a blood smear (Balduini et al, 2003). The latter test is performed by May–Grünwald–Giemsa (MGG) staining or through the identification. We describe the phenotypic profiles of this MYH9‐RD cohort, adding new insight into genotype–phenotype correlations and expanding the knowledge of this rare inherited platelet disorder

| METHODS

| RESULTS

| DISCUSSION

FUNDING INFORMATION

Findings

DATA AVAILABILITY STATEMENT