GFI1 – Severe Congenital Neutropenia

The association between the growth factor independent 1 (GFI1) gene and severe congenital neutropenia (SCN) is supported by multiple lines of evidence. Several studies have identified dominant negative mutations in GFI1 that impair its transcriptional repressor function, thereby perturbing granulocyte differentiation. This disruption contributes to the development of SCN, a condition characterized by extremely low neutrophil counts and recurrent infections (PMID:12778173).

Genetic evidence stems from the identification of pathogenic variants in unrelated probands with SCN. In one key report, a dominant mutation, for example, c.1208A>G (p.Lys403Arg), was observed in affected individuals, supporting an autosomal dominant mode of inheritance. Segregation analyses in family studies further substantiate that the mutation co‐segregates with the disorder, with multiple affected individuals exhibiting the variant (PMID:12778173).

Additional case reports and series have documented a consistent variant spectrum involving missense mutations that disrupt zinc finger domains critical for DNA binding. The genetic findings are bolstered by the observation that several probands and their affected relatives (with documented segregation in family studies) carry deleterious GFI1 variants, reinforcing the gene–disease relationship (PMID:12778173).

Functional and experimental studies provide strong support for the pathogenicity of GFI1 mutations. In vitro assays have demonstrated that mutant GFI1 proteins exhibit reduced DNA binding and impaired repression of target genes such as ELA2, a known contributor to SCN pathogenesis. Moreover, murine models deficient in Gfi1 recapitulate the neutropenic phenotype, and rescue experiments restore granulopoietic activity, thereby validating the mechanistic link between GFI1 dysfunction and impaired myelopoiesis (PMID:18328744; PMID:12721361).

While some case reports did not detect GFI1 mutations in every instance of SCN, the convergence of genetic and functional evidence from multiple independent studies strongly supports its role in disease etiology. This robust dataset, despite minor discrepancies, exceeds the ClinGen scoring threshold for a strong association by integrating both variant-level data and experimental verification.

In summary, the substantial genetic evidence—including the recurrent c.1208A>G (p.Lys403Arg) variant—and concordant functional studies provide a coherent narrative that firmly establishes GFI1 as a key gene in the pathogenesis of severe congenital neutropenia. This association has significant clinical implications for diagnostic decision‑making, prognosis, and potential therapeutic targeting.

References

• Nature Genetics • 2003 • Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2 PMID:12778173
• Immunity • 2008 • Mutations in growth factor independent-1 associated with human neutropenia block murine granulopoiesis through colony stimulating factor-1 PMID:18328744
• Proceedings of the National Academy of Sciences of the United States of America • 2003 • Targets of the transcriptional repressor oncoprotein Gfi-1 PMID:12721361

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