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Autosomal dominant thrombocytopenia 2 (THC2) is characterized by mild to moderate platelet reduction and a predisposition to myeloid malignancies due to regulatory variants in ANKRD26. Patients typically present with platelet counts <100×10⁹/L and minimal bleeding. Dysfunction arises from monoallelic substitutions in the 5′ untranslated region (5′UTR) of ANKRD26 that disrupt RUNX1/FLI1 binding and prevent developmental silencing during megakaryopoiesis (PMID:21211618).
Genetic evidence includes six distinct 5′UTR point substitutions clustered within a conserved 19-bp element in eight unrelated families (8 families ([PMID:21211618])) and a recurrent c.-128G>T variant in a large Chinese pedigree of 10 affected individuals (10 probands ([PMID:32351539])). Segregation is observed in 19 additional affected relatives across multi-generational pedigrees. Both 5′UTR and coding-region truncating variants (e.g., c.105C>G (p.Tyr35Ter)) have been identified in sporadic AML, indicating clinical overlap with leukemia predisposition (PMID:28100250).
The variant spectrum comprises 5′UTR substitutions (c.-128G>T, c.-127A>T, c.-134G>A, c.-125T>G) and N-terminal truncating alleles (c.3G>A (p.Met1Ile), c.105C>G (p.Tyr35Ter), c.4227dup (p.Thr1410fs)). A founder effect is noted for c.-128G>T in multiple Chinese families (PMID:32351539).
Functional studies demonstrate that 5′UTR mutations abrogate RUNX1/FLI1 repression in reporter assays, leading to sustained ANKRD26 promoter activity (PMID:21211618). Patient‐derived megakaryocytes exhibit persistent ANKRD26 expression, hyperactive MPL/ERK signaling and impaired proplatelet formation, all of which are rescued by ERK inhibition (PMID:24430186).
Disease modeling in patient‐derived hiPSCs carrying heterozygous c.-128G>T faithfully retains the variant and megakaryocytic transcriptomic signature, providing a scalable platform for THC2 research (PMID:32979630). A complex structural WAC-ANKRD26 fusion has also been shown to drive gain-of-function expression and thrombocytopenia in a family refractory to short-read sequencing (PMID:33857290).
Conflicting evidence for a previously reported c.-140C>G variant shows normal platelet counts and unaltered ANKRD26 expression in carriers, supporting its benign classification (PMID:39212265). Emerging data reveal an ANKRD26–ETV6–GPS2 axis that modulates transcriptional repression during megakaryopoiesis, offering insight into shared mechanisms among thrombocytopenia syndromes (PMID:39791724).
Key take-home: Definitive evidence supports AD ANKRD26 variants in THC2, with established guidelines recommending targeted testing of the 5′UTR in patients with unexplained thrombocytopenia to inform diagnosis, surveillance and donor selection for transplantation.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong19 probands with AD variants; segregation in 19 relatives; recurrent 5′UTR and truncating alleles Functional EvidenceStrongMultiple reporter assays, patient megakaryocyte studies, ERK‐inhibition rescue, hiPSC and structural variant models |