Novel PRRT2 gene variants identified in paroxysmal kinesigenic dyskinesia and benign familial infantile epilepsy in Chinese families

He,Jialinzi; Tang,Haiyun; Liu,Chaorong; Tan,Langzi; Xiao,Wenbiao; Xiao,Bo; Long,Hongyu; Long,Lili

doi:10.3892/etm.2021.9935

Novel PRRT2 gene variants identified in paroxysmal kinesigenic dyskinesia and benign familial infantile epilepsy in Chinese families

Authors:
- Jialinzi He
- Haiyun Tang
- Chaorong Liu
- Langzi Tan
- Wenbiao Xiao
- Bo Xiao
- Hongyu Long
- Lili Long
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Affiliations: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
Published online on: March 18, 2021 https://doi.org/10.3892/etm.2021.9935
Article Number: 504
Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study was performed to investigate the clinical manifestations and pathogenic variants in three large families with autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) and/or benign familial infantile epilepsy (BFIE) in China. Detailed clinical data and family history were collected. Genomic DNA was isolated from the peripheral blood samples of all available members. The genetic diagnosis was made by whole‑exome sequencing on the three probands and the candidate variants were verified by PCR‑Sanger sequencing. The pathogenicity of variants was predicted by bioinformatics analyses and classified according to the American College of Medical Genetics criteria. A total of three causative heterozygous variants were identified in the proline‑rich transmembrane protein 2 (PRRT2) gene by DNA sequencing: A novel c.324_334del(p.Val109Argfs*21) deletion variant in Family A, as well as the previously known c.510_513del(p.Ser172Argfs*3) deletion variant in Family B and c.649dupC(p.Arg217Profs*8) duplication variant in Family C. The three variants of PRRT2 co‑segregated with the phenotype and genotype in the family members. The present results deepen the current understanding of PKD/BFIE and extend the genotypic‑phenotypic spectrum of PKD/BFIE.

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1	Lu JG, Bishop J, Cheyette S, Zhulin IB, Guo S, Sobreira N and Brenner SE: A novel PRRT2 pathogenic variant in a family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures. Cold Spring Harb Mol Case Stud. 4(a002287)2018.PubMed/NCBI View Article : Google Scholar
2	Chen WJ, Lin Y, Xiong ZQ, Wei W, Ni W, Tan GH, Guo SL, He J, Chen YF, Zhang Q, et al: Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet. 43:1252–1255. 2011.PubMed/NCBI View Article : Google Scholar
3	Bhatia KP: Paroxysmal dyskinesias. Mov Disord. 26:1157–1165. 2011.PubMed/NCBI View Article : Google Scholar
4	Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, Hallett M, Jankovic J, Jinnah HA, Klein C, et al: Phenomenology and classification of dystonia: A consensus update. Mov Disord. 28:863–873. 2013.PubMed/NCBI View Article : Google Scholar
5	van Vliet R, Breedveld G, de Rijk-van Andel J, Brilstra E, Verbeek N, Verschuuren-Bemelmans C, Boon M, Samijn J, Diderich K, van de Laar I, et al: PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions. Neurology. 79:777–784. 2012.PubMed/NCBI View Article : Google Scholar
6	Vigevano F, Fusco L, Di Capua M, Ricci S, Sebastianelli R and Lucchini P: Benign infantile familial convulsions. Eur J Pediatr. 151:608–612. 1992.PubMed/NCBI View Article : Google Scholar
7	Okumura A, Hayakawa F, Kato T, Kuno K, Negoro T and Watanabe K: Early recognition of benign partial epilepsy in infancy. Epilepsia. 41:714–717. 2000.PubMed/NCBI View Article : Google Scholar
8	Zeng Q, Yang X, Zhang J, Liu A, Yang Z, Liu X, Wu Y, Wu X, Wei L and Zhang Y: Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort. J Hum Genet. 63:9–18. 2018.PubMed/NCBI View Article : Google Scholar
9	Okumura A, Shimojima K, Kubota T, Abe S, Yamashita S, Imai K, Okanishi T, Enoki H, Fukasawa T, Tanabe T, et al: PRRT2 mutation in Japanese children with benign infantile epilepsy. Brain Dev. 35:641–646. 2013.PubMed/NCBI View Article : Google Scholar
10	Jiang YL, Yuan F, Yang Y, Sun XL, Song L and Jiang W: CHRNA4 variant causes paroxysmal kinesigenic dyskinesia and genetic epilepsy with febrile seizures plus? Seizure. 56:88–91. 2018.PubMed/NCBI View Article : Google Scholar
11	Usluer S, Kayserili MA, Eken AG, Yiş U, Leu C, Altmüller J, Thiele H, Nürnberg P, Sander T and Çağlayan SH: Association of a synonymous SCN1B variant affecting splicing efficiency with Benign Familial Infantile Epilepsy (BFIE). Eur J Paediatr Neurol. 21:773–782. 2017.PubMed/NCBI View Article : Google Scholar
12	Wang J, Gao H, Bao X, Zhang Q, Li J, Wei L, Wu X, Chen Y and Yu S: SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures. BMC Med Genet. 18(104)2017.PubMed/NCBI View Article : Google Scholar
13	Yin XM, Lin JH, Cao L, Zhang TM, Zeng S, Zhang KL, Tian WT, Hu ZM, Li N, Wang JL, et al: Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene. Hum Mol Genet. 27:625–637. 2018.PubMed/NCBI View Article : Google Scholar
14	Ebrahimi-Fakhari D, Saffari A, Westenberger A and Klein C: The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain. 138:3476–3495. 2015.PubMed/NCBI View Article : Google Scholar
15	Rossi P, Sterlini B, Castroflorio E, Marte A, Onofri F, Valtorta F, Maragliano L, Corradi A and Benfenati F: A Novel Topology of Proline-rich transmembrane protein 2 (PRRT2): Hints for an intracellular function at the synapse. J Biol Chem. 291:6111–6123. 2016.PubMed/NCBI View Article : Google Scholar
16	Pruitt KD, Tatusova T and Maglott DR: NCBI Reference Sequences (RefSeq): A curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 33:D501–D504. 2005.PubMed/NCBI View Article : Google Scholar
17	Li H and Durbin R: Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics. 25:1754–1760. 2009.PubMed/NCBI View Article : Google Scholar
18	Verma M, Kulshrestha S and Puri A: Genome Sequencing. Methods Mol Biol. 1525:3–33. 2017.PubMed/NCBI View Article : Google Scholar
19	Kumar S, Stecher G and Tamura K: MEGA7: Molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol Biol Evol. 33:1870–1874. 2016.PubMed/NCBI View Article : Google Scholar
20	Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al: Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Meds. 17:405–424. 2015.PubMed/NCBI View Article : Google Scholar
21	Riggs ER, Andersen EF, Kantarci S, Kearney H, Patel A, Raca G, Ritter DI, South ST, Thorland EC, Pineda-Alvarez D, et al: Response to Maya et al. Genet Med. 22:1278–1279. 2020.PubMed/NCBI View Article : Google Scholar
22	Ma H, Feng S, Deng X, Wang L, Zeng S, Wang C, Ma X, Sun H, Chen R, Du S, et al: A PRRT2 variant in a Chinese family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures results in loss of interaction with STX1B. Epilepsia. 59:1621–1630. 2018.PubMed/NCBI View Article : Google Scholar
23	Chen GH: Five cases of paroxysmal kinesigenic dyskinesia by genetic diagnosis. Exp Ther Med. 9:909–912. 2015.PubMed/NCBI View Article : Google Scholar
24	Lee HY, Huang Y, Bruneau N, Roll P, Roberson ED, Hermann M, Quinn E, Maas J, Edwards R, Ashizawa T, et al: Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep. 1:2–12. 2012.PubMed/NCBI View Article : Google Scholar
25	Zhao G, Liu X, Zhang Q and Wang K: PRRT2 mutations in a cohort of Chinese families with paroxysmal kinesigenic dyskinesia and genotype-phenotype correlation reanalysis in literatures. Int J Neurosci. 128:751–760. 2018.PubMed/NCBI View Article : Google Scholar
26	Heron SE, Grinton BE, Kivity S, Afawi Z, Zuberi SM, Hughes JN, Pridmore C, Hodgson BL, Iona X, Sadleir LG, et al: PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet. 90:152–160. 2012.PubMed/NCBI View Article : Google Scholar
27	Marini C, Conti V, Mei D, Battaglia D, Lettori D, Losito E, Bruccini G, Tortorella G and Guerrini R: PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine. Neurology. 79:2109–2114. 2012.PubMed/NCBI View Article : Google Scholar
28	Ishii A, Yasumoto S, Ihara Y, Inoue T, Fujita T, Nakamura N, Ohfu M, Yamashita Y, Takatsuka H, Taga T, et al: Genetic analysis of PRRT2 for benign infantile epilepsy, infantile convulsions with choreoathetosis syndrome, and benign convulsions with mild gastroenteritis. Brain Dev. 35:524–530. 2013.PubMed/NCBI View Article : Google Scholar
29	Li HF, Chen WJ, Ni W, Wang KY, Liu GL, Wang N, Xiong ZQ, Xu J and Wu ZY: PRRT2 mutation correlated with phenotype of paroxysmal kinesigenic dyskinesia and drug response. Neurology. 80:1534–1535. 2013.PubMed/NCBI View Article : Google Scholar
30	Cao L, Huang XJ, Zheng L, Xiao Q, Wang XJ and Chen SD: Identification of a novel PRRT2 mutation in patients with paroxysmal kinesigenic dyskinesias and c.649dupC as a mutation hot-spot. Parkinsonism Relat Disord. 18:704–706. 2012.PubMed/NCBI View Article : Google Scholar
31	Zhang Y, Li L, Chen W, Gan J and Liu ZG: Clinical characteristics and PRRT2 gene mutation analysis of sporadic patients with paroxysmal kinesigenic dyskinesia in China. Clin Neurol Neurosurg. 159:25–28. 2017.PubMed/NCBI View Article : Google Scholar