Mutation Analysis of MR-1, SLC2A1, and CLCN1 in 28 PRRT2-negative Paroxysmal Kinesigenic Dyskinesia Patients

Abstract

Background:Paroxysmal kinesigenic dyskinesia (PKD) is the most common subtype of paroxysmal dyskinesias and is caused by mutations in PRRT2 gene. The majority of familial PKD was identified to harbor PRRT2 mutations. However, over two-third of sporadic PKD patients did not carry any PRRT2 mutation, suggesting an existence of additional genetic mutations or possible misdiagnosis due to clinical overlap.Methods:A cohort of 28 Chinese patients clinically diagnosed with sporadic PKD and excluded PRRT2 mutations were recruited. Clinical features were evaluated, and all subjects were screened for MR-1, SLC2A1, and CLCN1 genes, which are the causative genes of paroxysmal nonkinesigenic dyskinesia (PNKD), paroxysmal exertion-induced dyskinesia, and myotonia congenita (MC), respectively. In addition, 200 genetically matched healthy individuals were recruited as controls.Results:A total of 16 genetic variants including 4 in MR-1 gene, 8 in SLC2A1 gene, and 4 in CLCN1 gene were detected. Among them, SLC2A1 c.363G>A mutation was detected in one case, and CLCN1 c.1205C>T mutation was detected in other two cases. Neither of them was found in 200 controls as well as 1000 Genomes database and ExAC database. Both mutations were predicted to be pathogenic by SIFT and PolyPhen2. The SLC2A1 c.363G>A mutation was novel.Conclusions:The phenotypic overlap may lead to the difficulty in distinguishing PKD from PNKD and MC. For those PRRT2- negative PKD cases, screening of SLC2A1 and CLCN1 genes are useful in confirming the diagnosis.

Functional study and pathogenicity classification of PRRT2 missense variants in PRRT2‐related disorders

“…27.6% (8/29) of the variants were uncertain significance variants and their pathogenicity needs further investigation. New disease‐causing genetic mutations are waiting to be discovered in these patients with benign PRRT2 variants or without PRRT2 variants …”

Paroxysmal motor disorders: expanding phenotypes lead to coalescing genotypes

“…Conversely, across the broad category of paroxysmal movement disorders multiple genes may converge on similar phenotypes. For example, though PKD is typically associated with PRRT2 gene mutation, kinesigenic spells have also been described with mutation in SLC16A2, KCNA1, ADCY5 , SLC2A1, SCN8A, SLC20A2, and CLNC1 . Similarly, other clinical features have been associated with mutations in numerous genes.…”

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

“…It has been demonstrated to be associated with mutations in several genes, including PRRT2 (proline‐rich region transmembrane protein‐2) (Chen et al, 2011), SLC2A1 (solute carrier family 2, member 1), MR‐1 (myofibrillogenesis regulator 1), CLCN1 (chloride voltage‐gated channel 1) (Wang, Li, Liu, Wen, & Wu, 2016), SCN8A (sodium voltage‐gated channel alpha subunit 8) (Chen et al, 2015), and ADCY5 (adenylyl cyclase 5) (Gardella et al, 2016). PRRT2 is the most common known causative gene for PKD.…”