Inherited missense variants that affect GFI1B function do not necessarily cause bleeding diatheses

Oorschot, Rinske van; Marneth, Anna E.; Bergevoet, Saskia M.; Bergen, Maaike G.J.M. van; Peerlinck, Kathelijne; Lentaigne, Claire; Millar, Carolyn M.; Westbury, Sarah K; Favier, Rémi; Erber, Wendy N.; Turro, Ernest; Jansen, Joop H.; Ouwehand, Willem H.; McKinney, Harriet; Downes, Kate; Freson, Kathleen; Reijden, Bert A. van der

doi:10.3324/haematol.2018.207712

Cited by 8 publications

(10 citation statements)

References 15 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The phenotype depends on the site and nature of the mutation and the GFI1B isoform affected. 46 Haploinsufficiency or non-functioning of GATA1 or GFI1B will change the activation of a number of genes coding for proteins maintaining platelet function.…”

Section: Gray Platelet Syndrome and Related Disordersmentioning

confidence: 99%

“…125,126 The use of NGS and high-throughput procedures for diagnosing platelet disorders including thrombocytopenias has quickly expanded worldwide as is illustrated by reports from Italy, Japan, Spain, France, Holland and Scandinavia as well as North America. 46,60,77,78,80,87,108,113,128,129 The question now is not whether to apply NGS procedures in the mainstream of diagnosis but when and how. 128 Certainly, a strong argument can now be made to use them upfront: early identification of a causal mutation in a known gene will avoid much unnecessary biological characterization, as we have stated recently in this journal.…”

Section: Diagnosismentioning

confidence: 99%

See 1 more Smart Citation

Inherited thrombocytopenias: history, advances and perspectives

Nurden

2020

Haematologica

View full text Add to dashboard Cite

In the late 19 th century improvements to the light microscope led to anucleate platelets being visualized in great numbers in human blood. Early pioneers in the field of platelet research included the Canadian William Osler, a Paris hematologist, George Hayem, who performed the first accurate platelet count, and the Italian Giulio Bizzozero. 1 In 1906, James Homer Wright confirmed that platelets were produced by bone marrow megakaryocytes. 2 When, in 1951, Harrington et al. 3 observed purpura in a child of a mother with immune thrombocytopenic purpura, a maternal factor was said to be destroying the platelets. Anti-platelet antibodies were identified as the cause and platelet transfusions, immunosuppressive therapy and splenectomy became standard treatments. Acquired thrombocytopenia, often with defective platelet function, has many causes. For example, it may be an immune response linked to blood transfusions and drugs, a direct consequence of viral or bacterial infections, be the result of other hematologic disorders or be secondary to many major illnesses. However, some thrombocytopenias are inherited and Professors Jean Bernard and Jean-Pierre Soulier in Paris were pioneers in this domain, describing in 1948 what they called in French "dystrophie thrombocytaire hémorragipare congénitale", later renamed the Bernard-Soulier syndrome (BSS). 4 Strikingly, many platelets were enlarged and some were giant. A key to the molecular defect was the platelet deficit of sialic acid, a negatively charged monosaccharide terminating many of the oligosaccharides of platelet glycoproteins (GP) and

show abstract

Section: Gray Platelet Syndrome and Related Disordersmentioning

confidence: 99%

Section: Diagnosismentioning

confidence: 99%

Inherited thrombocytopenias: history, advances and perspectives

Nurden

2020

Haematologica

View full text Add to dashboard Cite

show abstract

“…One individual heterozygous for the allele had an MPV of 12.5 fL, and in one family the mean platelet size among carriers was ∼30% larger compared to that in an unaffected family member, as measured by platelet diameter . Moreover, two individuals homozygous for the C168F mutation have been reported to have marked thrombocytopenia and abnormal platelet function, suggesting that this variant is indeed a loss‐of‐function or hypomorphic allele …”

Section: Resultsmentioning

confidence: 99%

“…2,9 Notably, the C168F GFI1B variant identified in our patient has been recently found to segregate in an autosomal dominant manner in three unrelated families with mild to moderate macrothrombocytopenia, but without significant bruising or bleeding symptoms. 10,11 Comparison of affected and unaffected relatives within each family suggests that the C168F mutation is associated with a decrease in platelet counts without signs of -granule deficiency, in contrast to other GFI1B mutations that result in changes in platelet granules. 10,12 Computational models predict that the C168F mutation changes the conformation of the first non-DNA-binding zinc finger domain.…”

Section: The C168f Variant In Gfi1bmentioning

confidence: 99%

“…Only one individual was homozygous for the C168F variant in the UK Biobank, so no density plot is shown for the TT genotype mutation have been reported to have marked thrombocytopenia and abnormal platelet function, suggesting that this variant is indeed a lossof-function or hypomorphic allele. 11,13 Given these findings, we decided to examine this variant within a large population-based study, the UK Biobank. 9,16 Within the UK Biobank, this variant has an allele frequency of 0.005487263 in individuals with South Asian ancestry.…”

Section: The C168f Variant In Gfi1bmentioning

confidence: 99%

See 1 more Smart Citation

Macrothrombocytopenia associated with a rare GFI1B missense variant confounding the presentation of immune thrombocytopenia

Cheng

Bao

Fiorini

et al. 2019

Pediatric Blood & Cancer

View full text Add to dashboard Cite

Growth factor‐independent 1B (GFI1B) variants are a rare cause of thrombocytopenia. We report on a male child who was initially diagnosed with immune thrombocytopenia. However, subtle clinical signs led to suspicion of a genetic cause of thrombocytopenia. Gene panel sequencing revealed a rare variant in GFI1B (C168F), which has recently been reported in several families with thrombocytopenia. We demonstrate that this variant significantly alters platelet parameters in population studies. This case highlights how diagnoses of exclusion, such as immune thrombocytopenia, can be confounded by genetic variation. Our understanding of blood disorders will undoubtedly evolve from an increased knowledge of human genetic variation.

show abstract