Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Combined alpha-delta platelet storage pool deficiency is characterized by the absence or reduction of both alpha granules and dense bodies in platelets, leading to variable bleeding severity. Genetic studies have implicated GFI1B, a zinc finger transcriptional repressor essential for megakaryocyte and erythroid maturation, as a causative gene. In a 2017 cohort, two unrelated patients exhibited combined alpha-delta granule deficiency linked to GFI1B mutations ([PMID:28041820]). One patient harbored heterozygous de novo or familial variants disrupting zinc-finger binding, and the other carried hypomorphic biallelic alleles causing autosomal recessive inheritance ([PMID:28041820]). These findings underscore GFI1B’s dosage-sensitive role in platelet granule biogenesis. The dual inheritance patterns facilitate diagnosis across dominant and recessive presentations.
Genetic evidence includes 2 probands ([PMID:28041820]), with one additional affected relative segregating a heterozygous variant ([PMID:28041820]). Reported variants comprise two missense alleles (c.548G>A (p.Arg183Gln); c.923T>C (p.Leu308Pro)) and one nonsense allele (c.793A>T (p.Lys265Ter)). The Arg183Gln change alters a non-DNA-binding zinc-finger, abrogating promoter association, while Lys265Ter truncates the fifth zinc-finger domain. Control databases show these variants to be absent or extremely rare, consistent with pathogenicity. Under ClinGen criteria, the genetic evidence is Limited given the small number of cases and modest segregation.
Functional assessments demonstrate that Arg183Gln and other GFI1B variants impair zinc-finger binding to cognate promoters, resulting in derepression of granule biogenesis genes ([PMID:28041820]). Electrophoretic mobility shift and reporter assays confirmed loss of DNA binding by mutant proteins. Abrogated transcriptional repression leads to defective granule protein expression and abnormal platelet morphology in vitro. These data are concordant with patient phenotypes, providing Moderate functional evidence per ClinGen standards. No conflicting studies dispute GFI1B’s role in this disorder.
The mechanism of disease involves haploinsufficiency for dominant alleles and hypomorphic loss-of-function for recessive alleles, consistent with GFI1B’s dosage sensitivity in megakaryopoiesis. Both dominant-negative and recessive effects converge on disrupted granule formation. Clinical utility of GFI1B testing is supported by characteristic platelet granule defects and aberrant CD34 expression. Identification of GFI1B variants informs differential diagnosis of inherited storage pool deficiencies, guiding genetic counseling and management. Functional promoter-binding assays serve as confirmatory diagnostic tests. Future work may refine genotype–phenotype correlations and therapeutic approaches for granule restoration.
Key take-home: GFI1B mutations underlie combined alpha-delta platelet storage pool deficiency via disrupted transcriptional repression of granule biogenesis genes, supporting its diagnostic and mechanistic relevance in inherited bleeding disorders.
Gene–Disease AssociationModerate2 probands, 1 segregated family, concordant functional data Genetic EvidenceLimited2 probands with heterozygous and biallelic variants; modest segregation Functional EvidenceModerateIn vitro assays show loss of zinc-finger promoter binding consistent with granule defects |