Although thrombocytopenia in neonatal intensive care patients is rarely due to inherited disorders, the number of genetic variants implicated in platelet defects has grown dramatically with increasing genome-wide sequencing. Here we describe a case of severe, oligogenic neonatal thrombocytopenia and reinterpret a reportedly benign mutation that is likely pathogenic. Despite this patient's synonymous mutation (GFI1B 576 C>T, Phe192=) being annotated as benign, GFI1B is a well-known regulator of megakaryopoiesis, this variant alters splicing and megakaryocyte maturation, and our analysis of existing genome-wide associated studies demonstrates that it likely causes gray platelet syndrome. This variant has not been reported in a case of life-threatening thrombocytopenia. We propose that the severity of this patient's phenotype is due to synergistic epistasis between the intrinsic platelet defect caused by this mutation and her concomitant inherited PMM2 congenital glycosylation disorder neither of which have been associated with such a severe phenotype. This case highlights the importance of whole-exome/genome sequencing for critically ill patients, reexamining variant interpretation when clinically indicated, and the need to study diverse genetic variation in hematopoiesis.
Keywords: Case report; GFI1B; PMM2 congenital disorder of glycosylation; oligogenic; thrombocytopenia.
What is the context? Low platelets (thrombocytopenia) in the neonatal population is not frequently inherited. As we perform unbiased DNA sequencing in more patients, the number of inherited platelet disorders and implicated variants is growing.The gene GFI1B encodes for a transcription factor that regulates megakaryocytes, the cell type that produces platelets. A synonymous substitution in GFI1B (576 C>T, Phe192=) is annotated as benign; however, experimental studies have shown that it inhibits megakaryocyte production.There is growing appreciation for oligogenic inheritance, where multiple causal variants contribute to clinical phenotypes.What is new? We present a case of life-threatening neonatal macrothrombocytopenia (large, hypogranulated sparse platelets) that has an oligogenic cause. We reinterpret the synonymous substitution GFI1B 576 C>T as pathogenic.This patient’s severe phenotype was likely due to the combined effect of GFI1B 576 C>T and her inherited glycosylation disorder (PMM2-CDG). Neither variant alone causes severe thrombocytopenia, but the combined intrinsic platelet defect (GFI1B mutation) and consumption (PMM2-CDG) likely produced her life-threatening phenotype.What is the impact? GFI1B is a critical regulator of megakaryocyte production. The purportedly benign mutation 576 C>T is likely pathogenic causing thrombocytopenia by impairing megakaryocyte maturation.As more patients have unbiased genome sequencing, oligogenic and polygenic inheritance will become increasingly appreciated as causes of platelet disorders.NICU providers should consider whole genome or exome sequencing of neonates with severe thrombocytopenia after reversible causes are ruled out.