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The correlation between multiple congenital anomalies hypotonia seizures syndrome 2 and PIGA: a case of novel PIGA germline variant and literature review

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Abstract

Background

PIGA (PIG class A) gene codes for the PIG-A protein, which is a catalytic subunit of GPI-GlcNAc transferase. GPI-anchored proteins play an important role in the metabolism of mammals. Somatic variants of PIGA genes in bone marrow hematopoietic stem cells often result in paroxysmal nocturnal haemoglobinuria, and the germline PIGA variants cause multiple congenital anomalies hypotonia seizures syndrome 2 (MCAHS2) because of glycosylphosphatidylinositol metabolic abnormalities.

Methods

Whole exome sequencing was performed on peripheral blood sample of the patient with MCAHS2. A novel germline PIGA variant was found, and Sanger sequencing was performed as verification for the variant. After that, we used the keywords to retrieve relevant reports and provided a literature review.

Results

A novel hemizygous germline PIGA variant (NM_002641.3:c.971G > A) at exon4 was identified through whole exome sequencing. And it was a highly probable pathogenic variant. Sanger sequencing yielded consistent results. The missense variant cause change of p.(Cys324Tyr) in the transcription product according to the predicted outcomes.

Conclusion

We reported a case of MCAHS2 caused by a novel PIGA variant. Following a review of the literature, we suggested that MCAHS2 should be considered as a disorder spectrum consisting of core symptoms, multi-system impairment, and premature death. The core symptoms include hypotonia, psychomotor delay, epilepsy (intractable epilepsy mostly) and early death. Core symptoms nearly happened to almost all patients. Meanwhile, MCAHS2 involves a wide range of organ and system impairments with changeable form.

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Acknowledgements

We thank the patient and their families for their selflessness in agreeing to publish patient’s clinical information. Thanks colleagues that studied under Professor Chunquan Cai for their help in the research process, especially Jie Zheng, Xiufang Zhi and Linjie Pu.

Funding

The present study was supported by National Natural Science Foundation of China [grant number 81771589], the Program of Tianjin Science and Technology Plan [grant no. 18ZXDBSY00170] and the Public Health and Technology project of Tianjin [grant no. ZC20120, TJWJ2021ZD007].

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Authors and Affiliations

  1. School of Basic Medical Science, Tianjin Medical University, 300070, Tianjin, China

    Xiangyu Liu

  2. Tianjin Children’s Hospital (Children’s Hospital of Tianjin University), No. 238 Longyan Road, Beichen District, 300134, Tianjin, China

    Jing Meng, Jinhui Ma, Jianbo Shu, Chunyu Gu, Xiaofang Chen, Dong Li & Chunquan Cai

  3. The Medical Department of Neurology, Tianjin Children’s Hospital, No. 238 Longyan Road, Beichen District, 300134, Tianjin, China

    Jing Meng, Jinhui Ma & Dong Li

  4. The Medical Department of Neurology Electroencephalogram room, Tianjin Children’s Hospital, 300134, Tianjin, China

    Jinhui Ma

  5. Tianjin Pediatric Research Institute, 300134, Tianjin, China

    Jianbo Shu & Chunquan Cai

  6. Graduate College of Tianjin Medical University, 300070, Tianjin, China

    Chunyu Gu & Xiaofang Chen

  7. Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, 300134, Tianjin, China

    Chunquan Cai

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  1. Xiangyu Liu
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Contributions

Xiangyu Liu and Jing Meng participated in the conception of the study and writing of the manuscript. Jinhui Ma made great contributions to clinical information collection of the case and provided abundant knowledge of electroencephalogram. Jianbo Shu, Xiangyu Liu, Jing Meng Chunyu Gu performed the experiments and provided the planning and analysis of the application of sequencing technology. Chunquan Cai, Dong Li and Xiaofang Chen made a review of previous literature. Chunyu Gu and Jing Meng revised the article critically for important intelectual cintent. Chunquan Cai revised the manuscript and submitted the manuscript. All of the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Dong Li or Chunquan Cai.

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Conflict of interest

The authors declare that there were not any financial or non-financial interests related to the work that could be constructed as a potential conflict of interest.

Ethics Statement

The study was approved by the Ethics Committee of Tianjin Children’s Hospital (Tianjin University Children’s Hospital). Written informed consent of the patient was obtained from his parents. All study procedures adhered to the tenets of the Declaration of Helsinki.

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Xiangyu Liu Jing Meng and Jinhui Ma were equally responsible for the work described in this work.

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Liu, X., Meng, J., Ma, J. et al. The correlation between multiple congenital anomalies hypotonia seizures syndrome 2 and PIGA: a case of novel PIGA germline variant and literature review. Mol Biol Rep 49, 10469–10477 (2022). https://doi.org/10.1007/s11033-022-07614-8

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  • DOI: https://doi.org/10.1007/s11033-022-07614-8

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