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

参考文献

[1] Nagamitsu S, Matsuishi T, Hashimoto K, Yamashita Y, Aihara M, Shimizu K, Mizuguchi M, Iwamoto H, Saitoh S, Hirano Y, Kato H, Fukuyama Y, Shimada M. Multicenter study of paroxysmal dyskinesias in Japan—clinical and pedigree analysis. Mov Disord 1999; 14(4): 658–663

[2] Bruno MK, Hallett M, Gwinn-Hardy K, Sorensen B, Considine E, Tucker S, Lynch DR, Mathews KD, Swoboda KJ, Harris J, Soong BW, Ashizawa T, Jankovic J, Renner D, Fu YH, Ptacek LJ. Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria. Neurology 2004; 63(12): 2280–2287

[3] Chen WJ, Lin Y, Xiong ZQ, Wei W, Ni W, Tan GH, Guo SL, He J, Chen YF, Zhang QJ, Li HF, Lin Y, Murong SX, Xu J, Wang N, Wu ZY. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011; 43(12): 1252–1255

[4] Méneret A, Grabli D, Depienne C, Gaudebout C, Picard F, Dürr A, Lagroua I, Bouteiller D, Mignot C, Doummar D, Anheim M, Tranchant C, Burbaud P, Jedynak CP, Gras D, Steschenko D, Devos D, Billette de Villemeur T, Vidailhet M, Brice A, Roze E. PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 2012; 79(2): 170–174

[5] Li HF, Chen WJ, Ni W, Wang KY, Liu GL, Wang N, Xiong ZQ, Xu J, Wu ZY. PRRT2 mutation correlated with phenotype of paroxysmal kinesigenic dyskinesia and drug response. Neurology 2013; 80(16): 1534–1535

[6] Huang XJ, Wang SG, Guo XN, Tian WT, Zhan FX, Zhu ZY, Yin XM, Liu Q, Yin KL, Liu XR, Zhang Y, Liu ZG, Liu XL, Zheng L, Wang T, Wu L, Rong TY, Wang Y, Zhang M, Bi GH, Tang WG, Zhang C, Zhong P, Wang CY, Tang JG, Lu W, Zhang RX, Zhao GH, Li XH, Li H, Chen T, Li HY, Luo XG, Song YY, Tang HD, Luan XH, Zhou HY, Tang BS, Chen SD, Cao L. The phenotypic and genetic spectrum of paroxysmal kinesigenic dyskinesia in China. Mov Disord 2020; 35(8): 1428–1437

[7] Heron SE, Grinton BE, Kivity S, Afawi Z, Zuberi SM, Hughes JN, Pridmore C, Hodgson BL, Iona X, Sadleir LG, Pelekanos J, Herlenius E, Goldberg-Stern H, Bassan H, Haan E, Korczyn AD, Gardner AE, Corbett MA, Gécz J, Thomas PQ, Mulley JC, Berkovic SF, Scheffer IE, Dibbens LM. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet 2012; 90(1): 152–160

[8] Lee HY, Huang Y, Bruneau N, Roll P, Roberson ED, Hermann M, Quinn E, Maas J, Edwards R, Ashizawa T, Baykan B, Bhatia K, Bressman S, Bruno MK, Brunt ER, Caraballo R, Echenne B, Fejerman N, Frucht S, Gurnett CA, Hirsch E, Houlden H, Jankovic J, Lee WL, Lynch DR, Mohammed S, Müller U, Nespeca MP, Renner D, Rochette J, Rudolf G, Saiki S, Soong BW, Swoboda KJ, Tucker S, Wood N, Hanna M, Bowcock AM, Szepetowski P, Fu YH, Ptáček LJ. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep 2012; 1(1): 2–12

[9] Gardiner AR, Bhatia KP, Stamelou M, Dale RC, Kurian MA, Schneider SA, Wali GM, Counihan T, Schapira AH, Spacey SD, Valente EM, Silveira-Moriyama L, Teive HA, Raskin S, Sander JW, Lees A, Warner T, Kullmann DM, Wood NW, Hanna M, Houlden H. PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine. Neurology 2012; 79(21): 2115–2121

[10] Scheffer IE, Grinton BE, Heron SE, Kivity S, Afawi Z, Iona X, Goldberg-Stern H, Kinali M, Andrews I, Guerrini R, Marini C, Sadleir LG, Berkovic SF, Dibbens LM. PRRT2 phenotypic spectrum includes sporadic and fever-related infantile seizures. Neurology 2012; 79(21): 2104–2108

[11] Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C. The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain 2015; 138(12): 3476–3495

[12] Friedman J, Olvera J, Silhavy JL, Gabriel SB, Gleeson JG. Mild paroxysmal kinesigenic dyskinesia caused by PRRT2 missense mutation with reduced penetrance. Neurology 2012; 79(9): 946–948

[13] 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, Oostra B, Bonifati V, Maat-Kievit A. PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions. Neurology 2012; 79(8): 777–784

[14] Li HF, Ni W, Xiong ZQ, Xu J, Wu ZY. PRRT2 c.649dupC mutation derived from de novo in paroxysmal kinesigenic dyskinesia. CNS Neurosci Ther 2013; 19(1): 61–65

[15] Zhang LM, An Y, Pan G, Ding YF, Zhou YF, Yao YH, Wu BL, Zhou SZ. Reduced penetrance of PRRT2 mutation in a Chinese family with infantile convulsion and choreoathetosis syndrome. J Child Neurol 2015; 30(10): 1263–1269

[16] Schubert J, Paravidino R, Becker F, Berger A, Bebek N, Bianchi A, Brockmann K, Capovilla G, Dalla Bernardina B, Fukuyama Y, Hoffmann GF, Jurkat-Rott K, Anttonen AK, Kurlemann G, Lehesjoki AE, Lehmann-Horn F, Mastrangelo M, Mause U, Müller S, Neubauer B, Püst B, Rating D, Robbiano A, Ruf S, Schroeder C, Seidel A, Specchio N, Stephani U, Striano P, Teichler J, Turkdogan D, Vigevano F, Viri M, Bauer P, Zara F, Lerche H, Weber YG. PRRT2 mutations are the major cause of benign familial infantile seizures. Hum Mutat 2012; 33(10): 1439–1443

[17] Becker F, Schubert J, Striano P, Anttonen AK, Liukkonen E, Gaily E, Gerloff C, Müller S, Heußinger N, Kellinghaus C, Robbiano A, Polvi A, Zittel S, von Oertzen TJ, Rostasy K, Schöls L, Warner T, Münchau A, Lehesjoki AE, Zara F, Lerche H, Weber YG. PRRT2-related disorders: further PKD and ICCA cases and review of the literature. J Neurol 2013; 260(5): 1234–1244

[18] Steinberger D, Weber Y, Korinthenberg R, Deuschl G, Benecke R, Martinius J, Müller U. High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa-responsive dystonia. Ann Neurol 1998; 43(5): 634–639

[19] Cohn AC, Toomes C, Potter C, Towns KV, Hewitt AW, Inglehearn CF, Craig JE, Mackey DA. Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations. Am J Ophthalmol 2007; 143(4): 656–662

[20] Begg CB. On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer Inst 2002; 94(16): 1221–1226

[21] Sorscher S. Ascertainment bias and estimating penetrance. JAMA Oncol 2018; 4(4): 587

[22] Ottman R, Winawer MR, Kalachikov S, Barker-Cummings C, Gilliam TC, Pedley TA, Hauser WA. LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology 2004; 62(7): 1120–1126

[23] Rosanoff MJ, Ottman R. Penetrance of LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology 2008; 71(8): 567–571

[24] Marsh AP, Heron D, Edwards TJ, Quartier A, Galea C, Nava C, Rastetter A, Moutard ML, Anderson V, Bitoun P, Bunt J, Faudet A, Garel C, Gillies G, Gobius I, Guegan J, Heide S, Keren B, Lesne F, Lukic V, Mandelstam SA, McGillivray G, McIlroy A, Méneret A, Mignot C, Morcom LR, Odent S, Paolino A, Pope K, Riant F, Robinson GA, Spencer-Smith M, Srour M, Stephenson SE, Tankard R, Trouillard O, Welniarz Q, Wood A, Brice A, Rouleau G, Attié-Bitach T, Delatycki MB, Mandel JL, Amor DJ, Roze E, Piton A, Bahlo M, Billette de Villemeur T, Sherr EH, Leventer RJ, Richards LJ, Lockhart PJ, Depienne C. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance. Nat Genet 2017; 49(4): 511–514

[25] Saporta MA, Zaros C, Cruz MW, André C, Misrahi M, Bonaïti-Pellié C, Planté-Bordeneuve V. Penetrance estimation of TTR familial amyloid polyneuropathy (type I) in Brazilian families. Eur J Neurol 2009; 16(3): 337–341

[26] Rijken JA, Niemeijer ND, Jonker MA, Eijkelenkamp K, Jansen JC, van Berkel A, Timmers HJLM, Kunst HPM, Bisschop PHLT, Kerstens MN, Dreijerink KMA, van Dooren MF, van der Horst-Schrivers ANA, Hes FJ, Leemans CR, Corssmit EPM, Hensen EF. The penetrance of paraganglioma and pheochromocytoma in SDHB germline mutation carriers. Clin Genet 2018; 93(1): 60–66

[27] Minikel EV, Vallabh SM, Lek M, Estrada K, Samocha KE, Sathirapongsasuti JF, McLean CY, Tung JY, Yu LP, Gambetti P, Blevins J, Zhang S, Cohen Y, Chen W, Yamada M, Hamaguchi T, Sanjo N, Mizusawa H, Nakamura Y, Kitamoto T, Collins SJ, Boyd A, Will RG, Knight R, Ponto C, Zerr I, Kraus TF, Eigenbrod S, Giese A, Calero M, de Pedro-Cuesta J, Haïk S, Laplanche JL, Bouaziz-Amar E, Brandel JP, Capellari S, Parchi P, Poleggi A, Ladogana A, O’Donnell-Luria AH, Karczewski KJ, Marshall JL, Boehnke M, Laakso M, Mohlke KL, Kähler A, Chambert K, McCarroll S, Sullivan PF, Hultman CM, Purcell SM, Sklar P, van der Lee SJ, Rozemuller A, Jansen C, Hofman A, Kraaij R, van Rooij JG, Ikram MA, Uitterlinden AG, van Duijn CM, Exome Aggregation Consortium (ExAC); Daly MJ, MacArthur DG. Quantifying prion disease penetrance using large population control cohorts. Sci Transl Med 2016; 8(322): 322ra9

[28] Li HF, Yang L, Yin D, Chen WJ, Liu GL, Ni W, Wang N, Yu W, Wu ZY, Wang Z. Associations between neuroanatomical abnormality and motor symptoms in paroxysmal kinesigenic dyskinesia. Parkinsonism Relat Disord 2019; 62: 134–140

[29] Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; the ACMG Laboratory Quality Assurance Committee. 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

[30] Wohlgemuth M, Lemmers RJ, Jonker M, van der Kooi E, Horlings CG, van Engelen BG, van der Maarel SM, Padberg GW, Voermans NC. A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1. Neurology 2018; 91(5): e444–e454

[31] Ma H, Feng S, Deng X, Wang L, Zeng S, Wang C, Ma X, Sun H, Chen R, Du S, Mao J, Zhang X, Ma C, Jiang H, Zhang L, Tang B, Liu JYA. 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

[32] Liu YT, Nian FS, Chou WJ, Tai CY, Kwan SY, Chen C, Kuo PW, Lin PH, Chen CY, Huang CW, Lee YC, Soong BW, Tsai JW. PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects. Oncotarget 2016; 7(26): 39184–39196

[33] Zhao SY, Li LX, Chen YL, Chen YJ, Liu GL, Dong HL, Chen DF, Li HF, Wu ZY. Functional study and pathogenicity classification of PRRT2 missense variants in PRRT2-related disorders. CNS Neurosci Ther 2020; 26(1): 39–46

[34] Tsai MH, Nian FS, Hsu MH, Liu WS, Liu YT, Liu C, Lin PH, Hwang DY, Chuang YC, Tsai JW. PRRT2 missense mutations cluster near C-terminus and frequently lead to protein mislocalization. Epilepsia 2019; 60(5): 807–817

[35] Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H. 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

[36] Rosenfeld JA, Coe BP, Eichler EE, Cuckle H, Shaffer LG. Estimates of penetrance for recurrent pathogenic copy-number variations. Genet Med 2013; 15(6): 478–481

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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