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Autosomal dominant macrothrombocytopenia is characterized by mild to moderate thrombocytopenia with enlarged platelets and variable mucocutaneous bleeding. Heterozygous variants in the platelet glycoprotein Ib alpha gene (GP1BA) are implicated in this phenotype, defining a monoallelic Bernard-Soulier syndrome spectrum separate from recessive forms. Genetic and functional data consistently support a strong gene–disease relationship.
A novel heterozygous c.176T>G (p.Leu59Arg) variant segregated with macrothrombocytopenia in a kindred of seven affected members (PMID:30332551). Affected individuals exhibited mild bleeding, platelet macrocytosis, and autosomal dominant transmission. Independently, a recurrent c.515C>T (p.Ala172Val) change was identified in six of twelve Italian families, present in ten affected subjects with reduced GPIbα expression on platelets (PMID:11222377).
Overall, at least 17 probands across seven unrelated families (PMID:30332551, PMID:11222377) and 19 additional affected relatives have been described, fulfilling robust co-segregation criteria for an autosomal dominant trait. Both variants localize to the leucine-rich repeat domain of GPIbα, critical for von Willebrand factor binding, and disrupt conserved hydrophobic residues.
In silico modeling of p.Leu59Arg predicts steric clashes and destabilization of the LRR motif, impairing receptor folding. Flow cytometry in carriers of p.Ala172Val demonstrates decreased surface levels of GPIbα and GPIX, consistent with defective complex assembly and accelerated platelet clearance.
No conflicting reports have emerged; all documented heterozygous GP1BA variants in macrothrombocytopenia show concordant autosomal dominant segregation and functional impact. This contrasts with biallelic inactivating GP1BA variants causing severe Bernard-Soulier syndrome with recessive inheritance.
Collectively, genetic segregation and experimental assays provide strong clinical validity for GP1BA in autosomal dominant macrothrombocytopenia. Heterozygous LRR-domain missense variants should be screened in patients with unexplained inherited macrothrombocytopenia, guiding diagnosis, bleeding risk assessment, and management.
Key Take-Home: GP1BA germline LRR mutations cause autosomal dominant macrothrombocytopenia with mild bleeding, warranting targeted genetic testing.
Gene–Disease AssociationStrong17 probands across 7 families; co-segregation in 19 affected relatives Genetic EvidenceStrong17 probands in 7 families with consistent autosomal dominant segregation, reaching the ClinGen genetic evidence cap Functional EvidenceModerateIn silico LRR destabilization and platelet flow cytometry show impaired receptor assembly and function |