Novel heterozygous FOXN1 mutation identified during newborn screening for severe combined immunodeficiency is associated with improving immune parameters

Laura Abrego Fuentes, Jenny Garkaby, Jessica Willett-Pachul, Abby Watts-Dickens, Meghan Fraser, V. Kim, C. Roifman
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Abstract

ABSTRACT Background: Forkhead-box protein N1 (FOXN1) plays a critical role in the proper development and function of thymic epithelial cells, required for T cell ontogeny. Homozygous variants in FOXN1 cause severe combined immunodeficiency (SCID), whereas heterozygous mutations are associated with variable presentations and over time, improving T cell function. Aim: To highlight the importance of broader genetic investigations to attain a definitive molecular diagnosis following abnormal newborn screening for SCID. Methods: Case report of a patient with immunodeficiency due to a novel de novo FOXN1 mutation. Results: The patient was identified following abnormal newborn screening for SCID in which T cell receptor excision circles were absent/very low. Initial immune investigations revealed severe T cell lymphopenia and poor lymphocyte function and she was diagnosed with T-B+NK+SCID. During work-up for hematopoietic stem cell transplantation, extensive genetic investigations identified a novel heterozygous mutation in FOXN1. A more conservative management approach was taken, and over the following months, the patient’s immune parameters improved. Conclusion: Newborn screening for SCID has facilitated the detection of SCID, as well as other T cell immunodeficiencies, before infectious complications and organ damage occur. Heterozygous mutations in FOXN1 are associated with more variable presentations including improving immune indices with age. Here, results of genetic investigations were essential for informing the management of this case. Statement of Novelty We report a novel heterozygous mutation in FOXN1, presenting initially as T-B+NK+ SCID with gradual improvement of immune parameters over time.
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在新生儿严重联合免疫缺陷筛查中发现的新型杂合FOXN1突变与改善免疫参数有关
摘要背景:叉头盒蛋白N1(FOXN1)在T细胞个体发育所需的胸腺上皮细胞的正常发育和功能中起着至关重要的作用。FOXN1中的纯合子变体会导致严重联合免疫缺陷(SCID),而杂合子突变与可变表现有关,并随着时间的推移而改善T细胞功能。目的:强调在新生儿SCID异常筛查后进行更广泛的基因调查以获得明确的分子诊断的重要性。方法:一例因新型FOXN1突变导致免疫缺陷的病例报告。结果:患者在新生儿SCID异常筛查后被确认,其中T细胞受体切除圈缺失/非常低。最初的免疫调查显示,她患有严重的T细胞淋巴细胞减少症和淋巴细胞功能低下,并被诊断为T-B+NK+SCID。在造血干细胞移植的检查过程中,广泛的遗传学研究在FOXN1中发现了一种新的杂合突变。采取了更保守的管理方法,在接下来的几个月里,患者的免疫参数有所改善。结论:新生儿SCID筛查有助于在感染并发症和器官损伤发生之前检测SCID以及其他T细胞免疫缺陷。FOXN1的杂合突变与更多的可变表现有关,包括随着年龄的增长免疫指数的改善。在这里,基因调查的结果对于告知该病例的管理至关重要。新颖性声明我们报道了FOXN1中的一种新的杂合突变,最初表现为T-B+NK+SCID,随着时间的推移,免疫参数逐渐改善。
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