Pasternak Yehonatan, Vong Linda, Merico Daniele, Abrego Fuentes Laura, Scott Ori, Sham Marina, Fraser Meghan, Watts-Dickens Abby, Willett Pachul Jessica, Kim Vy H D, Marshall Christian R, Scherer Stephen, Roifman Chaim M
Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada.
Canadian Centre for Primary Immunodeficiency and the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, The Hospital for Sick Children and Research Institute, Toronto, Ontario, Canada.
J Allergy Clin Immunol Glob. 2024 Apr 23;3(3):100267. doi: 10.1016/j.jacig.2024.100267. eCollection 2024 Aug.
Forkhead box protein N1 (FOXN1) transcription factor plays an essential role in the development of thymic epithelial cells, required for T-cell differentiation, maturation, and function. Biallelic pathogenic variants in cause severe combined immunodeficiency (SCID). More recently, heterozygous variants in identified by restricted gene panels, were also implicated with causing a less severe and variable immunodeficiency.
We undertook longitudinal follow-up and advanced genetic investigations, including whole exome sequencing and whole genome sequencing, of newborns with a heterozygous variant in
Five patients (3 female, 2 male) have been followed since they were first detected with low T-cell receptor excision circles during newborn screening for SCID. Patients underwent immune evaluation as well as genetic testing, including a primary immunodeficiency panel, whole exome sequencing, and whole genome sequencing in some cases.
Median follow-up time was 6.5 years. Initial investigations revealed low CD3 T lymphocytes in all patients. One patient presented with extremely low lymphocyte counts and depressed phytohemagglutinin responses leading to a tentative diagnosis of SCID. Over a period of 2 years, CD3 T-cell counts rose, although in some patients it remained borderline low. One of 5 children continues to experience recurrent upper respiratory infections and asthma episodes. The remaining are asymptomatic except for eczema in 2 of 5 cases. Lymphocyte proliferation responses to phytohemagglutinin were initially low in 3 patients but normalized by age 10 months. In 3 of 5 cases, T lymphocyte counts remain low/borderline low.
In cases of monoallelic variants, using whole exome sequencing and whole genome sequencing to rule out possible other significant pathogenic variants allowed us to proceed with confidence in a conservative manner, even in extreme cases consistent with newborn screen-positive early presentation of SCID.
叉头框蛋白N1（FOXN1）转录因子在胸腺上皮细胞发育中起关键作用，而胸腺上皮细胞是T细胞分化、成熟和发挥功能所必需的。FOXN1双等位基因致病性变异可导致严重联合免疫缺陷（SCID）。最近，通过受限基因检测板鉴定出的FOXN1杂合变异也与导致不太严重且表现多样的免疫缺陷有关。
我们对携带FOXN1杂合变异的新生儿进行了纵向随访和深入的基因研究，包括全外显子组测序和全基因组测序。
5例患者（3例女性，2例男性）自新生儿SCID筛查中首次检测到低T细胞受体切除环以来一直接受随访。患者接受了免疫评估以及基因检测，包括原发性免疫缺陷检测板，部分病例还进行了全外显子组测序和全基因组测序。
中位随访时间为6.5年。初始检查发现所有患者的CD3 T淋巴细胞水平较低。1例患者淋巴细胞计数极低且对植物血凝素反应低下，初步诊断为SCID。在2年的时间里，CD3 T细胞计数有所上升，尽管部分患者仍处于临界低值。5名儿童中有1名持续出现反复上呼吸道感染和哮喘发作。其余患者除5例中有2例出现湿疹外均无症状。3例患者对植物血凝素的淋巴细胞增殖反应最初较低，但在10个月龄时恢复正常。5例中有3例T淋巴细胞计数仍低/临界低值。
在单等位基因FOXN1变异的病例中，使用全外显子组测序和全基因组测序排除可能的其他重要致病变异，使我们能够放心地采取保守的处理方式，即使在与新生儿筛查阳性的SCID早期表现一致的极端病例中也是如此。
