Rare Missense Variants in KCNJ10 Are Associated with Paroxysmal Kinesigenic Dyskinesia.
KCNJ10
dystonia
exome
genetics
paroxysmal kinesigenic dyskinesia
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
04 Mar 2024
04 Mar 2024
Historique:
revised:
03
01
2024
received:
18
10
2023
accepted:
05
02
2024
medline:
4
3
2024
pubmed:
4
3
2024
entrez:
4
3
2024
Statut:
aheadofprint
Résumé
Although the group of paroxysmal kinesigenic dyskinesia (PKD) genes is expanding, the molecular cause remains elusive in more than 50% of cases. The aim is to identify the missing genetic causes of PKD. Phenotypic characterization, whole exome sequencing and association test were performed among 53 PKD cases. We identified four causative variants in KCNJ10, already associated with EAST syndrome (epilepsy, cerebellar ataxia, sensorineural hearing impairment and renal tubulopathy). Homozygous p.(Ile209Thr) variant was found in two brothers from a single autosomal recessive PKD family, whereas heterozygous p.(Cys294Tyr) and p.(Thr178Ile) variants were found in six patients from two autosomal dominant PKD families. Heterozygous p.(Arg180His) variant was identified in one additional sporadic PKD case. Compared to the Genome Aggregation Database v2.1.1, our PKD cohort was significantly enriched in both rare heterozygous (odds ratio, 21.6; P = 9.7 × 10 We demonstrated that both rare monoallelic and biallelic missense variants in KCNJ10 are associated with PKD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Sections du résumé
BACKGROUND
BACKGROUND
Although the group of paroxysmal kinesigenic dyskinesia (PKD) genes is expanding, the molecular cause remains elusive in more than 50% of cases.
OBJECTIVE
OBJECTIVE
The aim is to identify the missing genetic causes of PKD.
METHODS
METHODS
Phenotypic characterization, whole exome sequencing and association test were performed among 53 PKD cases.
RESULTS
RESULTS
We identified four causative variants in KCNJ10, already associated with EAST syndrome (epilepsy, cerebellar ataxia, sensorineural hearing impairment and renal tubulopathy). Homozygous p.(Ile209Thr) variant was found in two brothers from a single autosomal recessive PKD family, whereas heterozygous p.(Cys294Tyr) and p.(Thr178Ile) variants were found in six patients from two autosomal dominant PKD families. Heterozygous p.(Arg180His) variant was identified in one additional sporadic PKD case. Compared to the Genome Aggregation Database v2.1.1, our PKD cohort was significantly enriched in both rare heterozygous (odds ratio, 21.6; P = 9.7 × 10
CONCLUSIONS
CONCLUSIONS
We demonstrated that both rare monoallelic and biallelic missense variants in KCNJ10 are associated with PKD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Fondation Maladies Rares
Informations de copyright
© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Références
Bruno MK, Hallett M, Gwinn-Hardy K, Sorensen B, Considine E, Tucker S, et al. Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria. Neurology 2004;63(12):2280-2287.
Méneret A, Roze E. Paroxysmal movement disorders: an update. Rev Neurol 2016;172(8-9):433-445.
Garone G, Capuano A, Travaglini L, Graziola F, Stregapede F, Zanni G, et al. Clinical and genetic overview of paroxysmal movement disorders and episodic ataxias. Int J Mol Sci 2020;21(10):3603.
van Vliet R, Breedveld G, de Rijk-van AJ, Brilstra E, Verbeek N, Verschuuren-Bemelmans C, et al. PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions. Neurology 2012;79(8):777-784.
Méneret A, Grabli D, Depienne C, Gaudebout C, Picard F, Dürr A, et al. PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 2012;79(2):170-174.
Tian WT, Huang XJ, Mao X, Liu Q, Liu XL, Zeng S, et al. Proline-rich transmembrane protein 2-negative paroxysmal kinesigenic dyskinesia: clinical and genetic analyses of 163 patients. Mov Disord 2018;33(3):459-467.
Li HF, Chen YL, Zhuang L, Chen DF, Ke HZ, Luo WJ, et al. TMEM151A variants cause paroxysmal kinesigenic dyskinesia. Cell Discovery 2021;7:83.
Li YL, Lv WQ, Zeng YH, Chen YK, Wang XL, Yang K, et al. Exome-wide analyses in paroxysmal Kinesigenic dyskinesia confirm TMEM151A as a novel causative gene. Mov Disord 2021;37(3):641-643.
Tian WT, Zhan FX, Liu ZH, Liu Z, Liu Q, Guo XN, et al. TMEM151A variants cause paroxysmal kinesigenic dyskinesia: a large-sample study. Mov Disord 2021;37(3):545-552.
Wirth T, Méneret A, Drouot N, Rudolf G, Lagha Boukbiza O, Chelly J, et al. De novo mutation in TMEM151A and paroxysmal kinesigenic dyskinesia. Mov Disord 2022;37(5):1115-1117.
Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, et al. Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med 2009;360(19):1960-1970.
Heterozygous KCNJ10 variants affecting Kir4.1 channel cause paroxysmal kinesigenic dyskinesia [Internet]. 2023 [cité 5 oct 2023]. Disponible sur: https://www.researchsquare.com.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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 Med 2015;17(5):405-424.
Wirth T, Tranchant C, Drouot N, Keren B, Mignot C, Cif L, et al. Increased diagnostic yield in complex dystonia through exome sequencing. Parkinsonism Relat Disord 2020;74:50-56.
Backenroth D, Homsy J, Murillo LR, Glessner J, Lin E, Brueckner M, et al. CANOES: detecting rare copy number variants from whole exome sequencing data. Nucleic Acids Res 2014;42(12):e97.
Marras C, Lang A, van de Warrenburg BP, Sue CM, Tabrizi SJ, Bertram L, et al. Nomenclature of genetic movement disorders: recommendations of the international Parkinson and movement disorder society task force. Mov Disord 2016;31(4):436-437.
Steel D, Vezyroglou A, Barwick K, Smith M, Vogt J, Gibbon FM, et al. Both heterozygous and homozygous loss-of-function JPH3 variants are associated with a paroxysmal movement disorder. Mov Disord 2023;38(1):155-157.
Genis D, Ortega-Cubero S, San Nicolás H, Corral J, Gardenyes J, de Jorge L, et al. Heterozygous STUB1 mutation causes familial ataxia with cognitive affective syndrome (SCA48). Neurology 2018;91(21):e1988-e1998.
Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, et al. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain 2014;137(Pt 5):1323-1336.
Riant F, Roze E, Barbance C, Méneret A, Guyant-Maréchal L, Lucas C, et al. PRRT2 mutations cause hemiplegic migraine. Neurology 2012;79(21):2122-2124.
Huang HL, Zhang QX, Huang F, Long XY, Song Z, Xiao B, et al. TMEM151A variants associated with paroxysmal kinesigenic dyskinesia. Hum Genet 2023;142(8):1017-1028.
Heron SE, Grinton BE, Kivity S, Afawi Z, Zuberi SM, Hughes JN, et al. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet 2012;90(1):152-160.
Padmanabha H, Raghavendra K, Arunachal G, Nagaraj AR, Harishma RS, Nashi S, et al. Episodic ataxia in child with 16p11.2 deletion including PRRT2. Parkinsonism Relat Disord 2023;118:105955.
Sen K, Genser I, DiFazio M, DiSabella M. Haploinsufficiency of PRRT2 leading to familial hemiplegic migraine in chromosome 16p11.2 deletion syndrome. Neuropediatrics 2022;53(4):279-282.
Chen YL, Chen DF, Ke HZ, Zhao SY, Li HF, Wu ZY. Paroxysmal kinesigenic dyskinesia caused by 16p11.2 microdeletion and related clinical features. Neurol Genet 2022;8(2):e659.
Zhang H, Zhu L, Wang F, Wang R, Hong Y, Chen Y, et al. Novel KCNJ10 compound heterozygous mutations causing EAST/SeSAME-like syndrome compromise Potassium Channel function. Front Genet 2019;10:912.
Lopes CMB, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE. Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies. Neuron 2002;34(6):933-944.