Penetrance estimation of PRRT2 variants in paroxysmal kinesigenic dyskinesia and infantile convulsions

Abstract

Proline-rich transmembrane protein 2 (PRRT2) is the leading cause of paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), and infantile convulsions with choreoathetosis (ICCA). Reduced penetrance of PRRT2 has been observed in previous studies, whereas the exact penetrance has not been evaluated well. The objective of this study was to estimate the penetrance of PRRT2 and determine its influencing factors. We screened 222 PKD index patients and their available relatives, identified 39 families with pathogenic or likely pathogenic (P/LP) PRRT2 variants via Sanger sequencing, and obtained 184 PKD/BFIE/ICCA families with P/LP PRRT2 variants from the literature. Penetrance was estimated as the proportion of affected variant carriers. PRRT2 penetrance estimate was 77.6% (95% confidence interval (CI) 74.5%–80.7%) in relatives and 74.5% (95% CI 70.2%–78.8%) in obligate carriers. In addition, we first observed that penetrance was higher in truncated than in non-truncated variants (75.8% versus 50.0%, P = 0.01), higher in Asian than in Caucasian carriers (81.5% versus 68.5%, P = 0.004), and exhibited no difference in gender or parental transmission. Our results are meaningful for genetic counseling, implying that approximately three-quarters of PRRT2 variant carriers will develop PRRT2-related disorders, with patients from Asia or carrying truncated variants at a higher risk.

Keywords

penetrance / PRRT2 / paroxysmal kinesigenic dyskinesia / infantile convulsions

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Acknowledgements

This study is supported by the grants to Zhi-Ying Wu (No. 81330025) and Hongfu Li (No. 81500973) from the National Natural Science Foundation of China, and the research foundation for distinguished scholar of Zhejiang University to Zhi-Ying Wu (No. 188020-193810101/089). We sincerely thank the subjects for their willingness to participate in this study and Ms. Wanqing Xu for her assistance in grammar of manuscript.

Compliance with ethics guidelines

Yulan Chen, Dianfu Chen, Shaoyun Zhao, Gonglu Liu, Hongfu Li, and Zhi-Ying Wu declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all subjects for being included in the study.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-021-0863-4 and is accessible for authorized users.

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