Paroxysmal Kinesigenic Dyskinesia Caused by 16p11.2 Microdeletion

Gao

et al. 2021

Front. Mol. Neurosci.

Epilepsy is one of the most common neurological disorders in pediatric patients with other underlying neurological defects. Identifying the underlying etiology is crucial for better management of the disorder. We performed trio-whole exome sequencing in 221 pediatric patients with epilepsy. Probands were divided into seizures with developmental delay/intellectual disability (DD/ID) and seizures without DD/ID groups. Pathogenic (P) or likely pathogenic (LP) variants were identified in 71/110 (64.5%) patients in the seizures with DD/ID group and 21/111 (18.9%) patients in the seizures without DD/ID group (P < 0.001). Eighty-seven distinct P/LP single nucleotide variants (SNVs)/insertion deletions (Indels) were detected, with 55.2% (48/87) of them being novel. All aneuploidy and P/LP copy number variants (CNVs) larger than 100 Kb were identifiable by both whole-exome sequencing and copy number variation sequencing (CNVseq) in 123 of individuals (41 pedigrees). Ten of P/LP CNVs in nine patients and one aneuploidy variant in one patient (Patient #56, #47, XXY) were identified by CNVseq. Herein, we identified seven genes (NCL, SEPHS2, PA2G4, SLC35G2, MYO1C, GPR158, and POU3F1) with de novo variants but unknown pathogenicity that were not previously associated with epilepsy. Potential effective treatment options were available for 32 patients with a P/LP variant, based on the molecular diagnosis. Genetic testing may help identify the molecular etiology of early onset epilepsy and DD/ID and further aid to choose the appropriate treatment strategy for patients.

Section: Discussionsupporting

confidence: 94%

Application of Trio-Whole Exome Sequencing in Genetic Diagnosis and Therapy in Chinese Children With Epilepsy

Gao

et al. 2021

Front. Mol. Neurosci.

“…To date, more than 400 patients with 16p11.2 deletions have been reported. Only six of these cases have been reported to have PKD (Dale, Grattan‐Smith, Fung, & Peters, ; Dale, Grattan‐Smith, Nicholson, & Peters, ; Lipton & Rivkin, ; Silveira‐Moriyama et al, ; Termsarasab et al, ; Weber, Kohler, Hahn, Neubauer, & Muller, ). The deletion ranges and phenotypes of these patients with PKD are summarized in Figure .…”

Section: Resultsmentioning

confidence: 99%

“…In previous studies, a 593‐kb deletion at map position B29.5–B30.1 Mb in the proximal region of 16p11.2 was defined as a typical 16p11.2 deletion commonly associated with symptoms of brain developmental abnormalities, while a 220‐kb deletion at map position B28.74–B28.95 Mb in the distal region was defined as an atypical 16p11.2 deletion featured by severe obesity due to the involvement of the SH2B1 gene, which plays a role in leptin and insulin signaling. PKD patients with PRRT2 CNVs all had the proximal 16p11.2 deletions (Dale et al, ; Lipton & Rivkin, ; Silveira‐Moriyama et al, ; Termsarasab et al, ; Weber et al, ). The overlapping region of the deletions contains two known causative genes— PRRT2 and KIF22 .…”

Section: Discussionmentioning

confidence: 99%

16p11.2 deletion in patients with paroxysmal kinesigenic dyskinesia but without intellectual disability

Wang

et al. 2018

Brain and Behavior

IntroductionMutations of the PRRT2 gene are the most common cause for paroxysmal kinesigenic dyskinesia. However, patients with negative PRRT2 mutations are not rare. The aim of this study is to determine whether copy number variant of PRRT2 gene is another potential pathogenic mechanism in the patients with paroxysmal kinesigenic dyskinesia with negative PRRT2 point and frameshift mutations.MethodsWe screened PRRT2 copy number variants using the AccuCopy™ method in 29 patients with paroxysmal kinesigenic dyskinesia with negative PRRT2 point and frameshift mutations. Next‐generation sequencing was used to determine the chromosomal deletion sites in patients with PRRT2 copy number variants, and to exclude mutations in other known causative genes for paroxysmal kinesigenic dyskinesia.ResultsTwo sporadic patients with negative PRRT2 point and frameshift mutations (6.9%) were identified to have de novo PRRT2 copy number deletions (591 and 832 Kb deletions located in 16p11.2). The two patients presented with pure paroxysmal kinesigenic dyskinesia and paroxysmal kinesigenic dyskinesia and benign infantile convulsions, respectively. They had normal intelligence and neuropsychiatric development, in contrast to those previously reported with 16p11.2 deletions complicated with neuropsychiatric disorders. No correlation between the deletion ranges and phenotypic variations was found.Conclusion16p11.2 deletions play causative roles in paroxysmal kinesigenic dyskinesia, especially for sporadic cases. Our findings extend the phenotype of 16p11.2 deletions to pure paroxysmal kinesigenic dyskinesia. Screening for 16p11.2 deletions should thus be included in genetic evaluations for patients with paroxysmal kinesigenic dyskinesia.

Journal of Pediatric Neurology

“…Generally, these patients present multiple congenital abnormalities, developmental delay, epilepsy, autism spectrum disorder, obesity, and psychiatric illnesses 11,[115][116][117][118][119] and also developmental delay, intellectual disability, and/or autism spectrum disorder. 28,30,120,121 Structural mutations at 16p11.2 has been associated to schizophrenia. 122 No clear evidence for genotype-phenotype correlations exists for PKD, BFIE, PKD with IC and HM.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

PRRT2 Related Epilepsies: A Gene Review

Massimino

Portale

Sapuppo

et al. 2021

PRRT2 encodes for proline-rich transmembrane protein 2 involved in synaptic vesicle fusion and presynaptic neurotransmitter release. Mutations in human PRRT2 have been related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with choreoathetosis, benign familial infantile epilepsies, and hemiplegic migraine. PRRT2 mutations cause neuronal hyperexcitability, which could be related to basal ganglia or cortical circuits dysfunction, leading to paroxysmal disorders. PRRT2 is expressed in the cerebral cortex, basal ganglia, and cerebellum. Approximately, 90% of pathogenic variants are inherited and 10% are de novo. Paroxysmal attacks in PKD are characterized by dystonia, choreoathetosis, and ballismus. In the benign familial infantile epilepsy (BFIE), seizures are usually focal with or without generalization, usually begin between 3 and 12 months of age and remit by 2 years of age. In 30% of cases of PRRT2-associated PKD, there is an association with BFIE, and this entity is referred to as PKD with infantile convulsions (PKD/IC). PRRT2 mutations are the cause of benign family childhood epilepsy and PKD/IC. On the other hand, PRRT2 mutations do not seem to correlate with other types of epilepsy. The increasing incidence of hemiplegic migraine in families with PRRT2-associated PKD or PKD/IC suggests a common disease pathway, and it is possible to assert that BFIE, paroxysmal kinesigenic dyskinesia, and PKD with IC belong to a continuous disease spectrum of PRRT2-associated diseases.