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E1021K Homozygous Mutation in PIK3CD Leads to Activated PI3K-Delta Syndrome 1

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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.

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Acknowledgments

We thank the patients and their families for taking part in the study. We also thank the doctors, nurses, and other health care providers at the Children’s Hospital of Chongqing Medical University. We thank the staffs of Chigene (Beijing) Translational Medical Research Center Co. Ltd. for providing next-generation sequencing, analyzing genetic diseases, and discussion.

Funding

This work was supported by the Natural Science Foundation of China (81974255).

Author information

Authors and Affiliations

  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

    Yanping Wang, Xuemei Chen, Qiuyun Yang, Yanjun Jia, Lina Zhou & Xiaodong Zhao

  2. Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Yanping Wang, Xuemei Chen, Qiuyun Yang, Yanjun Jia, Lina Zhou & Xiaodong Zhao

  3. Division of Rheumatology and Immunology, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Wenjing Tang, Yunfei An, Zhiyong Zhang, Xuemei Tang & Xiaodong Zhao

Authors
  1. Yanping Wang
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  2. Xuemei Chen
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  10. Xiaodong Zhao
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Contributions

Y. W., X. C., Q. Y., and W. T. performed the experiments and analyzed the data. Y. J. and L. Zhou provided help in performing the research. Y. A., Z. Z., and X. T. managed the patients. Y. W. and X. Z. wrote the manuscript. X. Z. designed the study and provided the financial support.

Corresponding author

Correspondence to Xiaodong Zhao.

Ethics declarations

Informed consent was obtained from all the participants. This study was conducted in accordance with the tenets of the Declaration of Helsinki and was approved by the ethics committee of Chongqing Medical University. All animal work was reviewed and approved by the Institutional Animal Care and Usage Committee of the Children’s Hospital of Chongqing Medical University.

Conflict of Interest

The authors declare that they have no competing interests.

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Wang, Y., Chen, X., Yang, Q. et al. E1021K Homozygous Mutation in PIK3CD Leads to Activated PI3K-Delta Syndrome 1. J Clin Immunol 40, 378–387 (2020). https://doi.org/10.1007/s10875-020-00749-y

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  • DOI: https://doi.org/10.1007/s10875-020-00749-y

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