Targeted genomic sequencing identifies PRRT2 mutations as a cause of paroxysmal kinesigenic choreoathetosis.

BACKGROUND: Paroxysmal kinesigenic choreoathetosis (PKC) is characterised by recurrent and brief attacks of involuntary movement, inherited as an autosomal dominant trait with incomplete penetrance. A PKC locus has been previously mapped to the pericentromeric region of chromosome 16 (16p11.2-q12.1), but the causative gene remains unidentified. METHODS/RESULTS: Deep sequencing of this 30 Mb region enriched with array capture in five affected individuals from four Chinese PKC families detected two heterozygous PRRT2 insertions (c.369dupG and c.649dupC), producing frameshifts and premature stop codons (p.S124VfsX10 and p.R217PfsX8, respectively) in two different families. Sanger sequencing confirmed these two mutations and revealed a missense PRRT2 mutation (c.859G→A, p.A287T) in one of the two remaining families. This study also sequenced PRRT2 in 29 sporadic cases affected with PKC and identified mutations in 10 cases, including six with the c.649dupC mutation. Most variants were truncating mutations, consistent with loss-of-function and haploinsufficiency. CONCLUSION: The present study identifies PRRT2 as the gene mutated in a subset of PKC, and suggests that PKC is genetically heterogeneous.

Localization and mutation detection for paroxysmal kinesigenic choreoathetosis.

BACKGROUND: Paroxysmal kinesigenic choreoathetosis (PKC) is an autosomal-dominant movement disorder characterized by attacks of paroxysmal involuntary movements. To date, the causative gene has not been discovered. PURPOSE: The purpose of the study is to localize the causative region and detect the causative mutation. METHODS: A PKC family including 16 subjects (5 cases and 11 controls) in Zhejiang Province was recruited. Nine microsatellite markers on chromosome 16 were selected and genotyped. Two-point LOD scores were calculated. After preliminary localization, CACNG3, IL4R and ABCC11 were selected as candidate genes and were detected by polymerase chain reaction-sequencing or PCR-denaturing high performance liquid chromatography (PCR-DHPLC). RESULTS: The maximal two-point LOD score was obtained in D16S3081 with 1.21, and haplotype analysis revealed almost all of individuals carrying 5-3-8-3-4-2-5-5-6 in D16S3093/D16S685/D16S690/D16S3081/D16S3080 D16S411/D16S3136/D16S3112/D16S3057 were affected by PKC. There were no causative mutation in CACNG3, IL4R and ABCC11 genes. CONCLUSIONS: The culprit gene for PKC was located in approximately 19.34 cM region between 16p12.1-q13, and CACNG3, IL4R and ABCC11 were all ruled out as the cause.