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Abstract：
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.
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.
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.
摘要：
尽管新生儿重症监护患者的血小板减少症很少是由于遗传性疾病，随着全基因组测序的增加,与血小板缺陷相关的遗传变异的数量急剧增加.在这里，我们描述了一个严重的案例，少基因新生儿血小板减少症，并重新解释可能致病的良性突变。尽管该患者具有同义突变（GFI1B576C>T，Phe192=)被注释为良性的，GFI1B是众所周知的巨核细胞生成调节因子，这种变异改变了剪接和巨核细胞成熟,我们对现有全基因组相关研究的分析表明，它可能导致灰色血小板综合征。在危及生命的血小板减少症的病例中尚未报道这种变体。我们认为，该患者表型的严重程度是由于该突变引起的内在血小板缺陷与她伴随的遗传性PMM2先天性糖基化障碍之间的协同上位所致，两者均未与这种严重表型相关。这个案例强调了全外显子组/基因组测序对危重病人的重要性。在临床上有指征时重新检查变体解释，以及需要研究造血中的各种遗传变异。
背景是什么？新生儿群中的低血小板（血小板减少症）不是经常遗传的。随着我们对更多患者进行无偏DNA测序，遗传性血小板疾病和相关变异的数量正在增加.基因GFI1B编码调节巨核细胞的转录因子，产生血小板的细胞类型。GFI1B中的同义替换(576C>T，Phe192=)被注释为良性的；然而，实验研究表明，它抑制巨核细胞的产生。人们对寡基因遗传的认识越来越高，其中多个因果变异导致临床表型。有什么新消息？我们提出一例危及生命的新生儿大血小板减少症（大，颗粒减少的稀疏血小板）具有寡基因原因。我们将同义替换GFI1B576C>T重新解释为致病性。该患者的严重表型可能是由于GFI1B576C>T和她的遗传性糖基化障碍(PMM2-CDG)的联合作用。两种变异都不能单独导致严重的血小板减少症，但固有血小板缺陷(GFI1B突变)和消耗(PMM2-CDG)联合可能产生了危及生命的表型.有什么影响？GFI1B是巨核细胞产生的关键调节因子。据称良性突变576C>T可能通过损害巨核细胞成熟而引起血小板减少症。随着越来越多的患者进行了无偏的基因组测序，寡基因和多基因遗传将越来越被认为是血小板疾病的原因。在排除可逆性原因后，NICU提供者应考虑对患有严重血小板减少症的新生儿进行全基因组或外显子组测序。
背景是什么？新生儿群中的低血小板（血小板减少症）不是经常遗传的。随着我们对更多患者进行无偏DNA测序，遗传性血小板疾病和相关变异的数量正在增加.基因GFI1B编码调节巨核细胞的转录因子，产生血小板的细胞类型。GFI1B中的同义替换(576C>T，Phe192=)被注释为良性的；然而，实验研究表明，它抑制巨核细胞的产生。人们对寡基因遗传的认识越来越高，其中多个因果变异导致临床表型。有什么新消息？我们提出一例危及生命的新生儿大血小板减少症（大，颗粒减少的稀疏血小板）具有寡基因原因。我们将同义替换GFI1B576C>T重新解释为致病性。该患者的严重表型可能是由于GFI1B576C>T和她的遗传性糖基化障碍(PMM2-CDG)的联合作用。两种变异都不能单独导致严重的血小板减少症，但固有血小板缺陷(GFI1B突变)和消耗(PMM2-CDG)联合可能产生了危及生命的表型.有什么影响？GFI1B是巨核细胞产生的关键调节因子。据称良性突变576C>T可能通过损害巨核细胞成熟而引起血小板减少症。随着越来越多的患者进行了无偏的基因组测序，寡基因和多基因遗传将越来越被认为是血小板疾病的原因。在排除可逆性原因后，NICU提供者应考虑对患有严重血小板减少症的新生儿进行全基因组或外显子组测序。
