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

Chen, Yulan; Chen, Dianfu; Zhao, Shaoyun; Liu, Gong‐Lu; Li, Hongfu; Wu, Zhi‐Ying

doi:10.1007/s11684-021-0863-4

Cited by 10 publications

(10 citation statements)

References 35 publications

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“…Detailed information of novel PRRT2 and TMEM151A variants is listed in Supplementary Table S1. Previously, we identified 78 probands with PRRT2 variants and 11 probands with TMEM151A variants 11,15 . Taken together, PRRT2 and TMEM151A variants accounted for 34.7% (85/245) and 6.9% (17/245) of PKD probands, respectively.…”

Section: Resultsmentioning

confidence: 73%

“…14 It is reported that PRRT2 variants in sporadic cases could be attributed to incomplete penetrance or de novo mutagenesis. 5,18,19 The penetrance of PRRT2 variants was estimated to be 74.5% to 77.6%, 15 and the rate of de novo mutagenesis was about 5.5%. 9 Regarding TMEM151A variants, we observed that 6 of 13 family members with TMEM151A variants were asymptomatic in this and the previous study.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we identified 78 probands with PRRT2 variants among 222 PKD probands 15 and performed whole‐exome sequencing (WES) in 36 probands negative for PRRT2 variants who had a family history or a favorable response to carbamazepine or oxcarbazepine by the 6‐month follow‐up 11 . Thus, the remaining 108 probands who have not been screened for TMEM151A variants were enrolled.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we identified 78 probands with PRRT2 variants and 11 probands with TMEM151A variants. 11,15 Taken together, PRRT2 and TMEM151A variants accounted for 34.7% (85/245) and 6.9% (17/245) of PKD probands, respectively. The TMEM151A variants accounted for 10.63% (17/160) of probands negative for PRRT2 variants.…”

Section: Genetic Featuresmentioning

confidence: 98%

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Features Differ Between Paroxysmal Kinesigenic Dyskinesia Patients with PRRT2 and TMEM151A Variants

Chen

et al. 2022

Movement Disorders

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Background: Mutations in prolinerich transmembrane protein 2 (PRRT2) are the major cause of paroxysmal kinesigenic dyskinesia (PKD). We recently reported transmembrane protein 151A (TMEM151A) mutations caused PKD. Herein, we aimed to conduct phenotypic comparisons of patients with PKD carrying PRRT2 variants, carrying TMEM151A variants, and carrying neither the PRRT2 nor TMEM151A variant. Methods: Sanger sequencing of PRRT2 and TMEM151A was performed, and phenotypic characteristics were analyzed. Results: In a cohort of 131 PKD probands (108 without PRRT2 variants and 23 newly recruited), five novel TMEM151A variants were identified and one (c.647C > A) occurred de novo. Together with our previous studies, PRRT2 and TMEM151A variants accounted for 34.7% (85/245) and 6.9% (17/245) of PKD probands, respectively. Compared with patients carrying PRRT2 variants, those with TMEM151A variants tended to exbibit dystonia with shorter durations, have no history of benign infantile epilepsy, and have residual attacks/aura when treated with carbamazepine/oxcarbazepine. Conclusions: Patients with TMEM151A variants have different features from patients with PRRT2 variants.

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Section: Resultsmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Genetic Featuresmentioning

confidence: 98%

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Features Differ Between Paroxysmal Kinesigenic Dyskinesia Patients with PRRT2 and TMEM151A Variants

Chen

et al. 2022

Movement Disorders

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“…The ClinGen Low Penetrance/Risk Allele Working Group Grinton 12 currently propose using risk allele to refer to "variants with very low penetrance that do not manifest in a Mendelian pattern of inheritance", while low or incomplete penetrance variants are conceptualized as those "that may have evidence of segregating in a Mendelian pattern" 40 . Large family studies facilitate this distinction, and indeed there are many examples of autosomal dominant epilepsies with incomplete penetrance [41][42][43] . With the most reliable penetrance estimates for the SCN1B c.363C>G variant being approximately 70%, coupled with the functional study evidence, the classification as a Mendelian "variant with incomplete penetrance" stands, however, we note that this is an evolving spectrum.…”

Section: Grintonmentioning

confidence: 99%

A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure

Grinton¹,

Robertson²,

Fearnley³

et al. 2022

The American Journal of Human Genetics

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Heterozygous Variants in KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia Via Haploinsufficiency

Li,

Lin,

Huang

et al. 2024

Annals of Neurology

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ObjectiveMost paroxysmal kinesigenic dyskinesia (PKD) cases are hereditary, yet approximately 60% of patients remain genetically undiagnosed. We undertook the present study to uncover the genetic basis for undiagnosed PKD patients.MethodsWhole‐exome sequencing was performed for 106 PRRT2‐negative PKD probands. The functional impact of the genetic variants was investigated in HEK293T cells and Drosophila.ResultsHeterozygous variants in KCNJ10 were identified in 11 individuals from 8 unrelated families, which accounted for 7.5% (8/106) of the PRRT2‐negative probands. Both co‐segregation of the identified variants and the significantly higher frequency of rare KCNJ10 variants in PKD cases supported impacts from the detected KCNJ10 heterozygous variants on PKD pathogenesis. Moreover, a KCNJ10 mutation‐carrying father from a typical EAST/SeSAME family was identified as a PKD patient. All patients manifested dystonia attacks triggered by sudden movement with a short episodic duration. Patch‐clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient‐derived variants, indicating a loss‐of‐function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock‐in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia‐specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes.InterpretationOur study established haploinsufficiency resulting from heterozygous variants in KCNJ10 can be understood as a previously unrecognized genetic cause for PKD and provided evidence of glial involvement in the pathophysiology of PKD. ANN NEUROL 2024

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

Cited by 10 publications

References 35 publications

Features Differ Between Paroxysmal Kinesigenic Dyskinesia Patients with PRRT2 and TMEM151A Variants

Features Differ Between Paroxysmal Kinesigenic Dyskinesia Patients with PRRT2 and TMEM151A Variants

A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure

Heterozygous Variants in KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia Via Haploinsufficiency

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