Yanping Wang1,2, Xuemei Chen1,2, Qiuyun Yang1,2, Wenjing Tang3, Yanjun Jia1,2, Lina Zhou1,2, Yunfei An3, Zhiyong Zhang3, Xuemei Tang3, Xiaodong Zhao4,5,6. 1. Department of Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. 2. Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China. 3. Division of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China. 4. Department of Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. zhaoxd530@aliyun.com. 5. Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China. zhaoxd530@aliyun.com. 6. Division of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China. zhaoxd530@aliyun.com.
Abstract
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.
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.
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