PURPOSE Activated PI3Kδ syndrome 1 is a primary immunodeficiency disease, usually caused by heterozygous mutations in PIK3CD. We aimed to identify the cause of homozygous mutation at c.G3061A (p.E1021K) in a patient and the effect of allele dose in this mutation. METHODS Genomic DNA from the parent-child trio was analyzed by next-generation sequencing. We performed phenotypic analyses in the patient and in Pik3cdE1024K+/+ mice. RESULTS The patient was a girl harboring a homozygous mutation for p.E1021K in PIK3CD. At the age of 2 months, she began experiencing respiratory tract infections and lymphoproliferation, accompanied by bronchiectasis and extensive atelectasis in the lungs. She suffered from Haemophilus influenzae and Cytomegalovirus infections and experienced restricted growth and development. Whole-exome sequencing showed a region that included PIK3CD, with loss of heterozygosity (LOH) in chromosome 1 of the patient. The patient had not inherited any allele from her father in the LOH region. Copy number variation analysis showed no changes in the patient's father and the patient. Ultra-deep sequencing of genomic DNA from the patient's mother showed that the mutant allele frequency for c.G3061A was 1.64%. Thus, the presence of segmental maternal uniparental disomy and maternal gonosomal mosaicism resulted in the homozygous mutation. Lymphadenopathy, differentiation of activated T cells, and follicular B cells lymphopenia were found to be more prominent in Pik3cdE1024+/+ mice than in Pik3cdE1024+/- mice. CONCLUSION This report showed the coexistence of uniparental disomy and mosaicism in PIK3CD. Some immunological features were seen to be allele dose-dependent in the presence of p.E1021K mutation.

中文翻译：

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PIK3CD 中的 E1021K 纯合突变导致激活的 PI3K-Delta 综合征 1。

目的 激活的 PI3Kδ 综合征 1 是一种原发性免疫缺陷疾病，通常由 PIK3CD 中的杂合突变引起。我们旨在确定患者 c.G3061A (p.E1021K) 纯合突变的原因以及等位基因剂量对这种突变的影响。方法通过二代​​测序分析来自亲子三人组的基因组DNA。我们在患者和 Pik3cdE1024K+/+ 小鼠中进行了表型分析。结果 该患者是一名女孩，在 PIK3CD 中存在 p.E1021K 纯合突变。在 2 个月大时，她开始出现呼吸道感染和淋巴组织增生，伴有支气管扩张和肺部广泛的肺不张。她患有流感嗜血杆菌和巨细胞病毒感染，生长发育受限。全外显子组测序显示一个包含 PIK3CD 的区域，患者的 1 号染色体具有杂合性丢失 (LOH)。该患者在 LOH 地区没有从她父亲那里继承任何等位基因。拷贝数变异分析显示患者的父亲和患者没有变化。来自患者母亲的基因组 DNA 的超深度测序显示 c.G3061A 的突变等位基因频率为 1.64%。因此，节段性母体单亲二体性和母体性染色体嵌合体的存在导致了纯合突变。淋巴结病、活化 T 细胞分化和滤泡 B 细胞淋巴细胞减少在 Pik3cdE1024+/+ 小鼠中比在 Pik3cdE1024+/- 小鼠中更为突出。结论 本报告显示 PIK3CD 中单亲二体性和嵌合体共存。