Background: Congenital thrombocytopenia is a highly heterogeneous disorder in both genetic cause and clinical phenotype. Confirmation of congenital thrombocytopenia is clinically important both for exclusion of ITP or other cause and for family studies. GFI1B is one of many genes associated with thrombocytopenia and codes for a zinc-finger containing transcription factor, primarily expressed in haematopoietic cells. A number of variants have been reported in GFI1B associated with thrombocytopenia.

Aims: Clarification of the role of GFI1B p.(Cys168Phe).

Methods: Almost 100 patients referred with thrombocytopenia / macrothrombocytopenia were analysed for the R90 Bleeding and Platelet disorder panel. Analysis was performed using a Twist Bioscience custom design panel run on a NovaSeq and the data analysed using Congenica. Putative pathogenic variants were confirmed by Sanger sequencing.

Results: Our laboratory has identified the c.503G>T; p.(Cys168Phe) variant in 15 index cases, including two homozygotes, from 12 families. This variant has been reported with a minor allele frequency of 0.4% in the South Asian population. The platelet count in this cohort was between 80-100 x 10^9/L, with large platelets observed in some patients.

Conclusion(s): Following the ACGS / ACMG guidelines this variant scores as a variant of uncertain significance, due to its high frequency in the South Asian population. This would not normally merit reporting as a diagnostic finding. However, our data confirms that this variant is significantly more common in individuals with mild thrombocytopenia than the ‘normal’ population. Given the reported MAF of 0.4%, 3000 individuals of South Asian heritage would require screening to identify 12 affected families. Rabbolini (2017) reported that this variant may be associated with a macrothrombocytopenia phenotype with no alpha-granule deficiency or bleeding symptoms. It is possible that this variant explains a mild thrombocytopenia but would not be sufficient to explain a significant bleeding phenotype. As such it should be reported in context.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/the-gfi1b-c-503gt-p-cys168phe-variant-a-diagnostic-conundrum/