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

doi:10.1007/s11684-021-0863-4

Frontiers of Medicine

2021, Vol. 15

Issue (6): 877-886 https://doi.org/10.1007/s11684-021-0863-4

本期目录

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

Yulan Chen¹, Dianfu Chen¹, Shaoyun Zhao¹, Gonglu Liu², Hongfu Li¹(

), Zhi-Ying Wu¹(

)

¹. Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310009, China
². Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China

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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.

Key words： penetrance PRRT2 paroxysmal kinesigenic dyskinesia infantile convulsions

收稿日期: 2020-12-29 出版日期: 2021-12-27

Corresponding Author(s): Hongfu Li,Zhi-Ying Wu

引用本文:

. [J]. Frontiers of Medicine, 2021, 15(6): 877-886.
Yulan Chen, Dianfu Chen, Shaoyun Zhao, Gonglu Liu, Hongfu Li, Zhi-Ying Wu. Penetrance estimation of PRRT2 variants in paroxysmal kinesigenic dyskinesia and infantile convulsions. Front. Med., 2021, 15(6): 877-886.

链接本文:

https://academic.hep.com.cn/fmd/CN/10.1007/s11684-021-0863-4
https://academic.hep.com.cn/fmd/CN/Y2021/V15/I6/877

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Tab.4

1	S Nagamitsu, T Matsuishi, K Hashimoto, Y Yamashita, M Aihara, K Shimizu, M Mizuguchi, H Iwamoto, S Saitoh, Y Hirano, H Kato, Y Fukuyama, M Shimada. Multicenter study of paroxysmal dyskinesias in Japan—clinical and pedigree analysis. Mov Disord 1999; 14(4): 658–663 https://doi.org/10.1002/1531-8257(199907)14:4<658::AID-MDS1016>3.0.CO;2-7 pmid: 10435504
2	MK Bruno, M Hallett, K Gwinn-Hardy, B Sorensen, E Considine, S Tucker, DR Lynch, KD Mathews, KJ Swoboda, J Harris, BW Soong, T Ashizawa, J Jankovic, D Renner, YH Fu, LJ Ptacek. Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria. Neurology 2004; 63(12): 2280–2287 https://doi.org/10.1212/01.WNL.0000147298.05983.50 pmid: 15623687
3	WJ Chen, Y Lin, ZQ Xiong, W Wei, W Ni, GH Tan, SL Guo, J He, YF Chen, QJ Zhang, HF Li, Y Lin, SX Murong, J Xu, N Wang, ZY Wu. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011; 43(12): 1252–1255 https://doi.org/10.1038/ng.1008 pmid: 22101681
4	A Méneret, D Grabli, C Depienne, C Gaudebout, F Picard, A Dürr, I Lagroua, D Bouteiller, C Mignot, D Doummar, M Anheim, C Tranchant, P Burbaud, CP Jedynak, D Gras, D Steschenko, D Devos, T Billette de Villemeur, M Vidailhet, A Brice, E Roze. PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 2012; 79(2): 170–174 https://doi.org/10.1212/WNL.0b013e31825f06c3 pmid: 22744660
5	HF Li, WJ Chen, W Ni, KY Wang, GL Liu, N Wang, ZQ Xiong, J Xu, ZY Wu. PRRT2 mutation correlated with phenotype of paroxysmal kinesigenic dyskinesia and drug response. Neurology 2013; 80(16): 1534–1535 https://doi.org/10.1212/WNL.0b013e31828cf7e1 pmid: 23535490
6	XJ Huang, SG Wang, XN Guo, WT Tian, FX Zhan, ZY Zhu, XM Yin, Q Liu, KL Yin, XR Liu, Y Zhang, ZG Liu, XL Liu, L Zheng, T Wang, L Wu, TY Rong, Y Wang, M Zhang, GH Bi, WG Tang, C Zhang, P Zhong, CY Wang, JG Tang, W Lu, RX Zhang, GH Zhao, XH Li, H Li, T Chen, HY Li, XG Luo, YY Song, HD Tang, XH Luan, HY Zhou, BS Tang, SD Chen, L Cao. The phenotypic and genetic spectrum of paroxysmal kinesigenic dyskinesia in China. Mov Disord 2020; 35(8): 1428–1437 https://doi.org/10.1002/mds.28061 pmid: 32392383
7	SE Heron, BE Grinton, S Kivity, Z Afawi, SM Zuberi, JN Hughes, C Pridmore, BL Hodgson, X Iona, LG Sadleir, J Pelekanos, E Herlenius, H Goldberg-Stern, H Bassan, E Haan, AD Korczyn, AE Gardner, MA Corbett, J Gécz, PQ Thomas, JC Mulley, SF Berkovic, IE Scheffer, LM Dibbens. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet 2012; 90(1): 152–160 https://doi.org/10.1016/j.ajhg.2011.12.003 pmid: 22243967
8	HY Lee, Y Huang, N Bruneau, P Roll, ED Roberson, M Hermann, E Quinn, J Maas, R Edwards, T Ashizawa, B Baykan, K Bhatia, S Bressman, MK Bruno, ER Brunt, R Caraballo, B Echenne, N Fejerman, S Frucht, CA Gurnett, E Hirsch, H Houlden, J Jankovic, WL Lee, DR Lynch, S Mohammed, U Müller, MP Nespeca, D Renner, J Rochette, G Rudolf, S Saiki, BW Soong, KJ Swoboda, S Tucker, N Wood, M Hanna, AM Bowcock, P Szepetowski, YH Fu, LJ Ptáček. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep 2012; 1(1): 2–12 https://doi.org/10.1016/j.celrep.2011.11.001 pmid: 22832103
9	AR Gardiner, KP Bhatia, M Stamelou, RC Dale, MA Kurian, SA Schneider, GM Wali, T Counihan, AH Schapira, SD Spacey, EM Valente, L Silveira-Moriyama, HA Teive, S Raskin, JW Sander, A Lees, T Warner, DM Kullmann, NW Wood, M Hanna, H Houlden. PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine. Neurology 2012; 79(21): 2115–2121 https://doi.org/10.1212/WNL.0b013e3182752c5a pmid: 23077024
10	IE Scheffer, BE Grinton, SE Heron, S Kivity, Z Afawi, X Iona, H Goldberg-Stern, M Kinali, I Andrews, R Guerrini, C Marini, LG Sadleir, SF Berkovic, LM Dibbens. PRRT2 phenotypic spectrum includes sporadic and fever-related infantile seizures. Neurology 2012; 79(21): 2104–2108 https://doi.org/10.1212/WNL.0b013e3182752c6c pmid: 23077018
11	D Ebrahimi-Fakhari, A Saffari, A Westenberger, C Klein. The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain 2015; 138(12): 3476–3495 https://doi.org/10.1093/brain/awv317 pmid: 26598493
12	J Friedman, J Olvera, JL Silhavy, SB Gabriel, JG Gleeson. Mild paroxysmal kinesigenic dyskinesia caused by PRRT2 missense mutation with reduced penetrance. Neurology 2012; 79(9): 946–948 https://doi.org/10.1212/WNL.0b013e318266fabf pmid: 22895590
13	R van Vliet, G Breedveld, J de Rijk-van Andel, E Brilstra, N Verbeek, C Verschuuren-Bemelmans, M Boon, J Samijn, K Diderich, I van de Laar, B Oostra, V Bonifati, A Maat-Kievit. PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions. Neurology 2012; 79(8): 777–784 https://doi.org/10.1212/WNL.0b013e3182661fe3 pmid: 22875091
14	HF Li, W Ni, ZQ Xiong, J Xu, ZY Wu. PRRT2 c.649dupC mutation derived from de novo in paroxysmal kinesigenic dyskinesia. CNS Neurosci Ther 2013; 19(1): 61–65 https://doi.org/10.1111/cns.12034 pmid: 23176561
15	LM Zhang, Y An, G Pan, YF Ding, YF Zhou, YH Yao, BL Wu, SZ Zhou. Reduced penetrance of PRRT2 mutation in a Chinese family with infantile convulsion and choreoathetosis syndrome. J Child Neurol 2015; 30(10): 1263–1269 https://doi.org/10.1177/0883073814556887 pmid: 25403460
16	J Schubert, R Paravidino, F Becker, A Berger, N Bebek, A Bianchi, K Brockmann, G Capovilla, B Dalla Bernardina, Y Fukuyama, GF Hoffmann, K Jurkat-Rott, AK Anttonen, G Kurlemann, AE Lehesjoki, F Lehmann-Horn, M Mastrangelo, U Mause, S Müller, B Neubauer, B Püst, D Rating, A Robbiano, S Ruf, C Schroeder, A Seidel, N Specchio, U Stephani, P Striano, J Teichler, D Turkdogan, F Vigevano, M Viri, P Bauer, F Zara, H Lerche, YG Weber. PRRT2 mutations are the major cause of benign familial infantile seizures. Hum Mutat 2012; 33(10): 1439–1443 https://doi.org/10.1002/humu.22126 pmid: 22623405
17	F Becker, J Schubert, P Striano, AK Anttonen, E Liukkonen, E Gaily, C Gerloff, S Müller, N Heußinger, C Kellinghaus, A Robbiano, A Polvi, S Zittel, TJ von Oertzen, K Rostasy, L Schöls, T Warner, A Münchau, AE Lehesjoki, F Zara, H Lerche, YG Weber. PRRT2-related disorders: further PKD and ICCA cases and review of the literature. J Neurol 2013; 260(5): 1234–1244 https://doi.org/10.1007/s00415-012-6777-y pmid: 23299620
18	D Steinberger, Y Weber, R Korinthenberg, G Deuschl, R Benecke, J Martinius, U Müller. High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa-responsive dystonia. Ann Neurol 1998; 43(5): 634–639 https://doi.org/10.1002/ana.410430512 pmid: 9585358
19	AC Cohn, C Toomes, C Potter, KV Towns, AW Hewitt, CF Inglehearn, JE Craig, DA Mackey. Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations. Am J Ophthalmol 2007; 143(4): 656–662 https://doi.org/10.1016/j.ajo.2006.12.038 pmid: 17306754
20	CB Begg. On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer Inst 2002; 94(16): 1221–1226 https://doi.org/10.1093/jnci/94.16.1221 pmid: 12189225
21	S Sorscher. Ascertainment bias and estimating penetrance. JAMA Oncol 2018; 4(4): 587 https://doi.org/10.1001/jamaoncol.2017.4573 pmid: 29285541
22	R Ottman, MR Winawer, S Kalachikov, C Barker-Cummings, TC Gilliam, TA Pedley, WA Hauser. LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology 2004; 62(7): 1120–1126 https://doi.org/10.1212/01.WNL.0000120098.39231.6E pmid: 15079011
23	MJ Rosanoff, R Ottman. Penetrance of LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology 2008; 71(8): 567–571 https://doi.org/10.1212/01.wnl.0000323926.77565.ee pmid: 18711109
24	AP Marsh, D Heron, TJ Edwards, A Quartier, C Galea, C Nava, A Rastetter, ML Moutard, V Anderson, P Bitoun, J Bunt, A Faudet, C Garel, G Gillies, I Gobius, J Guegan, S Heide, B Keren, F Lesne, V Lukic, SA Mandelstam, G McGillivray, A McIlroy, A Méneret, C Mignot, LR Morcom, S Odent, A Paolino, K Pope, F Riant, GA Robinson, M Spencer-Smith, M Srour, SE Stephenson, R Tankard, O Trouillard, Q Welniarz, A Wood, A Brice, G Rouleau, T Attié-Bitach, MB Delatycki, JL Mandel, DJ Amor, E Roze, A Piton, M Bahlo, T Billette de Villemeur, EH Sherr, RJ Leventer, LJ Richards, PJ Lockhart, C Depienne. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance. Nat Genet 2017; 49(4): 511–514 https://doi.org/10.1038/ng.3794 pmid: 28250454
25	MA Saporta, C Zaros, MW Cruz, C André, M Misrahi, C Bonaïti-Pellié, V Planté-Bordeneuve. Penetrance estimation of TTR familial amyloid polyneuropathy (type I) in Brazilian families. Eur J Neurol 2009; 16(3): 337–341 https://doi.org/10.1111/j.1468-1331.2008.02429.x pmid: 19364362
26	JA Rijken, ND Niemeijer, MA Jonker, K Eijkelenkamp, JC Jansen, A van Berkel, HJLM Timmers, HPM Kunst, PHLT Bisschop, MN Kerstens, KMA Dreijerink, MF van Dooren, ANA van der Horst-Schrivers, FJ Hes, CR Leemans, EPM Corssmit, EF Hensen. The penetrance of paraganglioma and pheochromocytoma in SDHB germline mutation carriers. Clin Genet 2018; 93(1): 60–66 https://doi.org/10.1111/cge.13055 pmid: 28503760
27	EV Minikel, SM Vallabh, M Lek, K Estrada, KE Samocha, JF Sathirapongsasuti, CY McLean, JY Tung, LP Yu, P Gambetti, J Blevins, S Zhang, Y Cohen, W Chen, M Yamada, T Hamaguchi, N Sanjo, H Mizusawa, Y Nakamura, T Kitamoto, SJ Collins, A Boyd, RG Will, R Knight, C Ponto, I Zerr, TF Kraus, S Eigenbrod, A Giese, M Calero, J de Pedro-Cuesta, S Haïk, JL Laplanche, E Bouaziz-Amar, JP Brandel, S Capellari, P Parchi, A Poleggi, A Ladogana, AH O’Donnell-Luria, KJ Karczewski, JL Marshall, M Boehnke, M Laakso, KL Mohlke, A Kähler, K Chambert, S McCarroll, PF Sullivan, CM Hultman, SM Purcell, P Sklar, SJ van der Lee, A Rozemuller, C Jansen, A Hofman, R Kraaij, JG van Rooij, MA Ikram, AG Uitterlinden, CM van Duijn, Exome Aggregation Consortium (ExAC); MJ Daly, DG MacArthur. Quantifying prion disease penetrance using large population control cohorts. Sci Transl Med 2016; 8(322): 322ra9 https://doi.org/10.1126/scitranslmed.aad5169 pmid: 26791950
28	HF Li, L Yang, D Yin, WJ Chen, GL Liu, W Ni, N Wang, W Yu, ZY Wu, Z Wang. Associations between neuroanatomical abnormality and motor symptoms in paroxysmal kinesigenic dyskinesia. Parkinsonism Relat Disord 2019; 62: 134–140 https://doi.org/10.1016/j.parkreldis.2018.12.029 pmid: 30635245
29	S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL; the ACMG Laboratory Quality Assurance Committee Rehm. 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 Med 2015; 17(5): 405–423 https://doi.org/10.1038/gim.2015.30 pmid: 25741868
30	M Wohlgemuth, RJ Lemmers, M Jonker, E van der Kooi, CG Horlings, BG van Engelen, SM van der Maarel, GW Padberg, NC Voermans. A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1. Neurology 2018; 91(5): e444–e454 https://doi.org/10.1212/WNL.0000000000005915 pmid: 29997197
31	H Ma, S Feng, X Deng, L Wang, S Zeng, C Wang, X Ma, H Sun, R Chen, S Du, J Mao, X Zhang, C Ma, H Jiang, L Zhang, B Tang, JYA Liu. A PRRT2 variant in a Chinese family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures results in loss of interaction with STX1B. Epilepsia 2018; 59(8): 1621–1630 https://doi.org/10.1111/epi.14511 pmid: 30009426
32	YT Liu, FS Nian, WJ Chou, CY Tai, SY Kwan, C Chen, PW Kuo, PH Lin, CY Chen, CW Huang, YC Lee, BW Soong, JW Tsai. PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects. Oncotarget 2016; 7(26): 39184–39196 https://doi.org/10.18632/oncotarget.9258 pmid: 27172900
33	SY Zhao, LX Li, YL Chen, YJ Chen, GL Liu, HL Dong, DF Chen, HF Li, ZY Wu. Functional study and pathogenicity classification of PRRT2 missense variants in PRRT2-related disorders. CNS Neurosci Ther 2020; 26(1): 39–46 pmid: 31124310
34	MH Tsai, FS Nian, MH Hsu, WS Liu, YT Liu, C Liu, PH Lin, DY Hwang, YC Chuang, JW Tsai. PRRT2 missense mutations cluster near C-terminus and frequently lead to protein mislocalization. Epilepsia 2019; 60(5): 807–817 https://doi.org/10.1111/epi.14725 pmid: 30980674
35	DN Cooper, M Krawczak, C Polychronakos, C Tyler-Smith, H Kehrer-Sawatzki. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet 2013; 132(10): 1077–1130 https://doi.org/10.1007/s00439-013-1331-2 pmid: 23820649
36	JA Rosenfeld, BP Coe, EE Eichler, H Cuckle, LG Shaffer. Estimates of penetrance for recurrent pathogenic copy-number variations. Genet Med 2013; 15(6): 478–481 https://doi.org/10.1038/gim.2012.164 pmid: 23258348

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