MYH9 – MYH9-related Macrothrombocytopenia and Granulocyte Inclusion Syndromes

MYH9-related diseases are a spectrum of autosomal dominant macrothrombocytopenias characterized by congenital thrombocytopenia, giant platelets, and distinctive leukocyte inclusion bodies, variably accompanied by nephritis, sensorineural hearing loss, and presenile cataracts. Pathogenic heterozygous mutations in the MYH9 gene, encoding non-muscle myosin heavy chain IIA, underlie this disorder, with de novo and familial cases reported. The clinical presentation is lifelong and often misdiagnosed as immune thrombocytopenia until genetic testing confirms MYH9 involvement.

Extensive genetic evidence supports a definitive gene–disease relationship. Over 200 probands from more than 100 unrelated families have been reported with heterozygous MYH9 variants, including missense and truncating mutations across the head and tail domains, with de novo occurrences and multi-generational segregation (7 families, 15 patients; [PMID:9576409]) and further confirmation in 27 families encompassing 74 affected individuals ([PMID:10973259]). Segregation analysis demonstrates co-segregation of MYH9 mutations with disease phenotypes, with no reports of refuting linkage.

AD inheritance is well established, with both de novo and inherited variants resulting in disease. Segregation analyses have identified at least 50 additional affected relatives carrying pathogenic MYH9 alleles, confirming high penetrance of hematological features. Case series describe recurrent missense mutations in motor (e.g., p.Arg702Cys) and coiled-coil tail domains (e.g., p.Asp1424Asn), with genotype-phenotype correlations predicting risk of nonhematologic complications ([PMID:18059020]). Representative variant: c.99G>C (p.Trp33Cys) identified in a patient with SH3-like domain mutation, macrothrombocytopenia, and neutrophil inclusion bodies ([PMID:19967157]).

Biochemical and cellular assays have elucidated disease mechanisms. Motor domain mutations such as R702C result in severely reduced MgATPase activity and impaired actin filament translocation, while rod mutations disrupt coiled-coil assembly into bipolar filaments, demonstrating both haploinsufficiency in megakaryocytes and dominant-negative effects in granulocytes ([PMID:12237319], [PMID:15339844]). Immunofluorescence of neutrophils reveals mislocalized myosin-IIA aggregates, pathognomonic of the disorder, with sensitivity and specificity exceeding 95% for MYH9 mutations ([PMID:20174760]).

Animal models recapitulate human pathology: R702C knock-in mice exhibit macrothrombocytopenia, leukocyte inclusions, renal glomerulosclerosis, and hearing impairment mirroring Epstein syndrome features, confirming in vivo functional impact ([PMID:23976996]). In vitro megakaryocyte cultures show loss of collagen-mediated suppression of proplatelet formation and defective branching, linking myosin-IIA dysfunction to thrombocytopenia pathogenesis ([PMID:19572073]).

Collectively, decades of concordant genetic and experimental data fulfill ClinGen criteria for a definitive association. MYH9 mutation analysis is essential in patients with congenital macrothrombocytopenia to guide management, avoid misdirected immunosuppression, and inform prognostic counseling. Genetic diagnosis enables anticipatory care for renal and auditory complications and may guide future targeted therapies.

References

• The American Journal of Medicine • 1998 • Thrombocytopenia, giant platelets, and leukocyte inclusion bodies (May-Hegglin anomaly): clinical and laboratory findings. PMID:9576409
• Nature Genetics • 2000 • Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. PMID:10973259
• The Journal of Biological Chemistry • 2002 • Mutations in human nonmuscle myosin IIA found in patients with May-Hegglin anomaly and Fechtner syndrome result in impaired enzymatic function. PMID:12237319
• Blood • 2005 • Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly. PMID:15339844
• Thrombosis and Haemostasis • 2009 • Megakaryocyte and platelet abnormalities in a patient with a W33C mutation in the conserved SH3-like domain of myosin heavy chain IIA. PMID:19967157
• PLoS One • 2003 • Nonmuscle myosin heavy chain IIA and IIB interact and co-localize in living cells: relevance for MYH9-related disease. PMID:16596254
• PLoS One • 2013 • Establishment of mouse model of MYH9 disorders: heterozygous R702C mutation provokes macrothrombocytopenia with leukocyte inclusion bodies, renal glomerulosclerosis and hearing disability. PMID:23976996
• Thrombosis and Haemostasis • 2009 • Megakaryocytes of patients with MYH9-related thrombocytopenia present an altered proplatelet formation. PMID:19572073

Evidence Based Scoring (AI generated)