Abstract
ABSTRACT
Background
Inherited platelet disorders (IPDs) are a heterogeneous group of diseases characterized by thrombocytopenia and/or platelet functional abnormalities. This study aimed to identify novel candidate genes associated with hereditary thrombocytopenia using whole‐exome sequencing (WES).
Methods
WES was performed in 40 patients with suspected IPDs. Functional characterization included segregation analysis, platelet‐based immunoblotting, and in silico structural modeling.
Results
Rare variants in known IPD‐associated genes were identified in 32 patients (80%). Reanalysis of unresolved cases identified a novel homozygous
ITGA10
(NM_003637.5) variant (c.2248C>T; p.Leu750Phe) in a 5‐year‐old female with severe thrombocytopenia.
ITGA10
encodes the α10 subunit of the α10β1 integrin complex and is located within the recurrent 1q21.1 microdeletion region associated with thrombocytopenia‐absent radius syndrome. Immunoblotting studies demonstrated mildly reduced ITGA10 expression, an additional ∼80 kDa ITGA10‐related band, markedly reduced ITGB1 expression, and absence of β‐actin expression in platelet lysates despite wild‐type
ACTB
and
ITGB1
genotypes. In silico structural analysis predicted reduced protein stability and impaired conformational flexibility associated with the p.Leu750Phe substitution.
Conclusions
These findings support ITGA10 as a novel candidate gene for inherited thrombocytopenia and suggest that disruption of the ITGA10–ITGB1 integrin complex may contribute to abnormal platelet homeostasis and cytoskeletal organization. Further functional studies and additional patients will be important to clarify the biological mechanisms and establish the role of ITGA10 in inherited thrombocytopenia.