PDF(Pubmed)
Abstract：
UNASSIGNED: 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 FOXN1 cause severe combined immunodeficiency (SCID). More recently, heterozygous variants in FOXN1, identified by restricted gene panels, were also implicated with causing a less severe and variable immunodeficiency.
UNASSIGNED: We undertook longitudinal follow-up and advanced genetic investigations, including whole exome sequencing and whole genome sequencing, of newborns with a heterozygous variant in FOXN1.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: In cases of monoallelic FOXN1 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.
UNASSIGNED: We undertook longitudinal follow-up and advanced genetic investigations, including whole exome sequencing and whole genome sequencing, of newborns with a heterozygous variant in FOXN1.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: In cases of monoallelic FOXN1 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.
摘要：
■叉头盒蛋白N1（FOXN1）转录因子在胸腺上皮细胞的发育中起着至关重要的作用，T细胞分化所必需的，成熟,和功能。FOXN1的双等位基因致病变异导致严重的联合免疫缺陷(SCID)。最近,FOXN1中的杂合变体，通过限制性基因小组鉴定，还涉及导致不太严重和可变的免疫缺陷。
■我们进行了纵向随访和高级遗传调查，包括全外显子组测序和全基因组测序，FOXN1中具有杂合变体的新生儿。
■5名患者（3名女性，2名男性），因为在新生儿SCID筛查期间首次检测到低T细胞受体切除圈。患者接受了免疫评估和基因检测，包括原发性免疫缺陷组,整个外显子组测序，在某些情况下全基因组测序。
■中位随访时间为6.5年。初步调查显示，所有患者的CD3+T淋巴细胞均较低。一名患者的淋巴细胞计数极低，植物血凝素反应低下，导致对SCID的初步诊断。在两年的时间里，CD3+T细胞计数上升，尽管在某些患者中，它仍然处于临界低位。5名儿童中的1名继续经历反复上呼吸道感染和哮喘发作。其余5例中的2例除湿疹外无症状。3例患者对植物血凝素的淋巴细胞增殖反应最初较低，但到10个月大时恢复正常。在5个案例中，有3个T淋巴细胞计数保持低/临界低。
■在单等位基因FOXN1变体的情况下，使用全外显子组测序和全基因组测序来排除可能的其他重要致病变异，使我们能够以保守的方式自信地进行，即使在极端情况下，与SCID的新生儿筛查阳性早期表现一致。
■我们进行了纵向随访和高级遗传调查，包括全外显子组测序和全基因组测序，FOXN1中具有杂合变体的新生儿。
■5名患者（3名女性，2名男性），因为在新生儿SCID筛查期间首次检测到低T细胞受体切除圈。患者接受了免疫评估和基因检测，包括原发性免疫缺陷组,整个外显子组测序，在某些情况下全基因组测序。
■中位随访时间为6.5年。初步调查显示，所有患者的CD3+T淋巴细胞均较低。一名患者的淋巴细胞计数极低，植物血凝素反应低下，导致对SCID的初步诊断。在两年的时间里，CD3+T细胞计数上升，尽管在某些患者中，它仍然处于临界低位。5名儿童中的1名继续经历反复上呼吸道感染和哮喘发作。其余5例中的2例除湿疹外无症状。3例患者对植物血凝素的淋巴细胞增殖反应最初较低，但到10个月大时恢复正常。在5个案例中，有3个T淋巴细胞计数保持低/临界低。
■在单等位基因FOXN1变体的情况下，使用全外显子组测序和全基因组测序来排除可能的其他重要致病变异，使我们能够以保守的方式自信地进行，即使在极端情况下，与SCID的新生儿筛查阳性早期表现一致。
