E1021K Homozygous Mutation in PIK3CD Leads to Activated PI3K-Delta Syndrome 1
E1021K Homozygous Mutation in PIK3CD Leads to Activated PI3K-Delta Syndrome 1
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DOI：
10.1007/s10875-020-00749-y
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发表时间：
2020-01
影响因子：
9.1
通讯作者：
Yanping Wang;Xuemei Chen;Qiuyun Yang;Wenjing Tang;Yanjun Jia;Lina Zhou;Y. An;Zhi-yong Zhang;Xuemei Tang;Xiaodong Zhao
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文献类型：
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作者：
Yanping Wang;Xuemei Chen;Qiuyun Yang;Wenjing Tang;Yanjun Jia;Lina Zhou;Y. An;Zhi-yong Zhang;Xuemei Tang;Xiaodong Zhao
目的活化型PI 3 K δ综合征1（Activated PI 3 K δ syndrome 1，ASS 1）是一种原发性免疫缺陷疾病，通常由PIK 3CD杂合突变引起。我们的目的是确定患者c.G3061A（p.E1021K）纯合突变的原因以及等位基因剂量对该突变的影响。方法通过下一代测序分析亲子三人组的基因组DNA。我们进行了患者和inPik 3cdE 1024 K +/+mice.ResultsThe患者是一个女孩窝藏p.E1021K inPIK 3CD纯合突变的表型分析。在2个月大时，她开始出现呼吸道感染和淋巴细胞增生，伴有支气管扩张和肺部广泛肺不张。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患者1号染色体存在PIK 3 CD的区域，伴有杂合性丢失（洛）。该患者在洛缺失区域没有从其父亲遗传任何等位基因。拷贝数变异分析显示患者父亲和患者均无变化。对患者母亲基因组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，节段性母本单亲二体性和母本生殖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细胞淋巴细胞减少症在Pik 3cdE 1024 +/+小鼠中比在Pik 3cdE 1024 +/−mice.ConclusionThis report showed the coexistence of unparental dishybrid and mosaicism in PIK 3 CD.在p.E1021K突变的存在下，一些免疫学特征被认为是等位基因剂量依赖性的。
PurposeActivated PI3Kδ syndrome 1 is a primary immunodeficiency disease, usually caused by heterozygous mutations inPIK3CD. 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.MethodsGenomic DNA from the parent-child trio was analyzed by next-generation sequencing. We performed phenotypic analyses in the patient and inPik3cdE1024K+/+mice.ResultsThe patient was a girl harboring a homozygous mutation for p.E1021K inPIK3CD. 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 fromHaemophilus influenzaeandCytomegalovirusinfections and experienced restricted growth and development. Whole-exome sequencing showed a region that includedPIK3CD, 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 inPik3cdE1024+/+mice than inPik3cdE1024+/−mice.ConclusionThis report showed the coexistence of uniparental disomy and mosaicism inPIK3CD. Some immunological features were seen to be allele dose-dependent in the presence of p.E1021K mutation.