Please wait a minute...
Shopping Cart Email List Chinese
Advanced Search Fig/Tab
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Featured Articles  |  Most Downloaded  |  Most Reading
Online Submission Subscribe to Our RSS Content Feed
Front. Med.    2021, Vol. 15 Issue (6) : 877-886    https://doi.org/10.1007/s11684-021-0863-4
RESEARCH ARTICLE
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
 Download: PDF(1061 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
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     
Corresponding Author(s): Hongfu Li,Zhi-Ying Wu   
Just Accepted Date: 31 August 2021   Online First Date: 25 November 2021    Issue Date: 27 December 2021
 Cite this article:   
Yulan Chen,Dianfu Chen,Shaoyun Zhao, et al. Penetrance estimation of PRRT2 variants in paroxysmal kinesigenic dyskinesia and infantile convulsions[J]. Front. Med., 2021, 15(6): 877-886.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0863-4
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I6/877
Variants Amino acid ?changes Frequency of population In silico prediction ACMG ?classification
1000 g ExAC gnomAD SIFT Polyphen-2
?(HumVar)		 Mutation
?Taster		 REVEL MetaLR
c.5C>T p.A2V Absent Absent Absent D D D T D US (PM2, PP3)
c.680G>A p.R227Q Absent 9.79E–06 1.36E–05 T P N T T US (PM2, BP4)
c.766delG p.V256Wfs*57 Absent Absent Absent D NA D NA NA Pathogenic ?(PVS1, PM2, ?PP3)
c.881C>T p.S294F Absent Absent Absent D D D D D US (PM2, PP3)
c.902G>C p.G301A Absent Absent Absent D D D D D US (PM2, PP3)
c.952_?953dupAT p.V319Sfs*19 Absent Absent Absent D NA D NA NA Pathogenic ?(PVS1, PM2, ?PP3)
c.962T>C p.L321P Absent Absent Absent D D D D D US (PM1, PM2, ?PP3)
c.976_?978delCTC p.L326del Absent 8.52E–06 1.23E–05 D NA D NA NA LP (PM1, PM2, ?PM4, PP3)
c.1012G>A p.V338M Absent 8.58E–06 4.17E–06 T B D T T US (PM1, PM2)
NatGene2 HSF NNSplice
c.879+ 4A>G NA Absent Absent Absent Donor site lost Donor site lost Donor site lost US (PM2, PP3)
Tab.1  Pathogenicity classification of 10 novel PRRT2 variants
Fig.1  PRRT2 variants identified in our 222 PKD index patients. (A) Diagram of PRRT2 variants superimposed to the domain structure of PRRT2 protein. PRRT2 contains 4 exons that encode a 340 amino acid protein. The “pathogenic/likely pathogenic” variants are labeled in red, and variants of “uncertain significance” are depicted in black. The number in the bracket represents the number of index patients carrying that variant. PRD, proline-rich domain; M1, transmembrane domain 1; M2, transmembrane domain 2; LOOP, domain between M1 and M2. (B) Chromatograms of 10 novel PRRT2 variants. The upper chromatogram in each frame represents the reference sequence, while the lower one represents the variant.
Fig.2  Flowchart of the study design and penetrance estimation.
Nucleotide change Protein change Number of ?families ?(n = 223) Number of ?affected/?variant ?carriersb Penetrance 1 Number of ?affected/?obligate ?carriers Penetrance 2
c.121_122delGT23 p.V41Tfs*92 1 4/5 0.8 1/2 0.5
c.133_136delCCAG25,a p.P45Rfs*44 2 0/2 0 0/2 0
c.186_187delGC22 p.P63Qfs*70 1 1/1 1 1/1 1
c.291delC4 p.N98Tfs*17 1 2/2 1 1/1 1
c.388delG12 p.A130Pfs*46 1 1/1 1 1/1 1
c.433delC6 p.R145Gfs*31 1 1/2 0.5 1/2 0.5
c.487C>T1 p.Q163X 1 5/7 0.71 3/3 1
c.514_517delTCTG19,a p.S172Rfs*3 2 3/4 0.75 2/3 0.67
c.604_607delTCAC24,a p.S202Hfs*26 2 4/5 0.8 2/2 1
c.621dupA27 p.S208Ifs*17 1 10/12 0.83 5/6 0.83
c.629dupC1 p.A211Sfs*14 1 3/3 1 2/2 1
c.629delC4 p.P210Qfs*19 1 4/7 0.57 1/3 0.33
c.649dupC1−9,11,14-20,23,25,26,28,29,a p.R217Pfs*8 173 427/536 0.80 237/307 0.77
c.649delC19−21,23,a p.R217Pfs*12 12 22/38 0.58 11/20 0.55
c.649C>T26,a p.R217X 2 2/2 1 2/2 1
c.697_698delAG20 p.S233Wfs*9 1 2/2 1 1/1 1
c.718C>T3,6,16,28,a p.R240X 6 18/19 0.95 9/10 0.9
c.741delC6 p.S248Afs*65 1 1/1 1 1/1 1
c.776dupG10,26 p.E260X 2 4/5 0.8 2/2 1
c.879+ 1G>T2,20 NA 2 3/5 0.6 1/2 0.5
c.880-2A>T5 NA 1 1/1 1 1/1 1
c.904_905insG19 p.D302Gfs*39 1 0/1 0 0/1 0
c.916G>A5 p.A306T 1 1/1 1 1/1 1
c.917C>A13 p.A306D 1 5/5 1 4/4 1
c.919C>T12 p.Q307X 1 0/1 0 0/1 0
c.950G>A2,28 p.S317N 2 11/22 0.5 3/13 0.23
c.971G>A5 p.G324E 1 2/2 1 1/1 1
c.976_978delCTCa p.L326del 1 1/1 1 1/1 1
Tab.2  Penetrance estimation of 28 PRRT2 variants identified in our and the published families
Combined Families??? P valuea
Our Published
All families, n 223 39 184
Total variant carriers (excluding index patients), n 693 61 632
?Affected, n 538 46 492
?Penetrance 1, % (95% CI) 77.6 (74.5–80.7) 75.4 (64.3–86.5) 77.8 (74.6–81.1) 0.663b
Total obligate carriers, n 396 43 353
?Affected, n 295 29 266
?Penetrance 2, % (95% CI) 74.5 (70.2–78.8) 67.4 (51.5–80.9) 75.4 (70.8–79.9) 0.261b
Tab.3  PRRT2 penetrance estimation in our and the published families
Obligate carriers, n Affected, n Penetrance, % (95% CI) P value
Variant type 0.01a
??Truncated variants 376 285 75.8 (71.4–80.1)
???Frameshift 355 267 75.2 (70.7–79.7)
???Nonsense 18 16 88.9 (65.3–98.6)
???Splice site 3 2 /
??Non-truncated variants 20 10 50.0 (27.2–72.8)
???Missense 19 9 47.4 (24.5–71.1)
???Non-frameshift deletion 1 1 /
Gender 0.271b
??Male 193 139 72.0 (65.6–78.4)
??Female 203 156 76.8 (71.0–82.7)
Parental transmission 0.334b
??Maternal 73 66 90.4 (83.5–97.3)
??Paternal 67 57 85.1 (76.3–93.8)
??Unknown 255 / /
??De novo 1 / /
Ethnic origin
??Asian 178 145 81.5 (75.7–87.2) 0.004c
??Caucasian 197 135 68.5 (62.0–75.1)
??African American 2 2 /
??Unknown 19 / /
Tab.4  PRRT2 penetrance by variant type, gender, parental transmission, and ethnic origin
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
[1] FMD-21017-OF-WZY_suppl_1 Download
[2] FMD-21017-OF-WZY_suppl_2 Download
[3] FMD-21017-OF-WZY_suppl_3 Download
[4] FMD-21017-OF-WZY_suppl_4 Download
[5] FMD-21017-OF-WZY_suppl_5 Download
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed