PB1283 - Determinants of genotype-phenotype correlations of MYH9 variants: lessons from patients with codon 1424 mutations.

Tuesday, June 25, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

LB

Leah Bhandal

Medical Student
University of Oxford
Leamington Spa, England, United Kingdom

Co-Author(s)

Susan Shapiro, MD, PhD

Associate Professor, Consultant Haematologist
Oxford University, Oxford University Hospitals
Oxford, England, United Kingdom
PB

Patricia Bignell

Consultant Clinical Scientist
Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Oxford, England, United Kingdom
CF

Carl Fratter

Consultant Clinical Scientist
Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Oxford, England, United Kingdom
José M Bastida

Hematologist
Departamento de Hematología, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Centro de Investigación del Cáncer, IBMCC-CSIC, Universidad de Salamanca (USAL), Salamanca, Spain. #Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC).
Salamanca, Castilla y Leon, Spain
MV

Miguel Vicente-Manzanares

Associate Professor of Research
M.V-M, Molecular Mechanisms Program, Centro de Investigación del Cáncer/ Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, 37007 Salamanca, Spain.
Salamanca, Castilla y Leon, Spain
DR

David Rabbolini

Honorary Senior Lecturer
Kolling Institute, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Sydney, New South Wales, Australia

Background: MYH9-related disease (MYH9-RD) is characterised by macrothrombocytopenia and a variable incidence of cataracts, nephropathy, and sensorineural deafness. Loose genotype-phenotype correlations have been asserted, however precise determinants of clinical phenotypes are unknown and have important prognostic potential.

Aims: To better define the variables that influence the genotype-phenotype relationship in individuals with MHY9-RD.

Methods: Literature review combined with data from the Oxford University Hospitals (OUH) was performed to determine the reported mutational spectrum and clinical phenotypes associated with the 6 most commonly altered residues of MYH9. This data will inform laboratory studies to resolve critical determinants of structural and subsequent functional change.

Results: The phenotypes of 151 patients with variants affecting MHY9 residues 96, 702, 1165, 1424, 1841, and 1933 were determined by analysis of 63 publications and OUH data (n=6) (Table 1.). The 1424 residue in the tail domain of MYH9 was most commonly mutated. Mutations causing one of several amino acid changes (e.g., R702C/H/S and D1424G/H/N/Y) were reported at residues 703 and 1424.
Conversely, mutations altering residues 96, 1165, 1841 and 1933 were conserved among patients, triggering a single amino acid substitution (S96L, R1165C, E1841K) or stop codon (R1933X). The incidence of sensorineural deafness, nephropathy and cataracts varied significantly by amino acid substitution at residue 1424. Moreover, D1424G and D1424H variants had a higher incidence of cataracts than S96 and R702S, R702C variants of the head domain of the protein (Table 1).

Conclusion(s): The genotype-phenotype correlation in MYH9-RD is not strictly limited to the site disrupted by the variant (head vs. tail), but also the effect of the variant at an amino acid residue. Ongoing studies will exploit cellular models to explore the pathophysiological determinants of variants in the head and tail domains. Data will be used to generate models that better predict the severity of disease. This will improve clinical management and prognostication.