Study of Pathogenic gene spectrum in benign familial infantile epilepsy

Abstract

Objective To investigate the gene mutations in benign familial infantile epilepsy(BFIE) in China. Methods Data of all BFIE probands and their family members were collected from Peking University First Hospital and other three hospitals between October 2006 and June 2017.Clinical phenotypes of affected members were analyzed.Genomic DNA was extracted from peripheral blood samples with standard protocol.Mutations in PRRT2 were screened using Sanger sequencing.For families that PRRT2 mutations were not detected by Sanger sequencing, candidate gene mutations were further screened by next-generation sequencing. Results A total of 71 families including 227 affected members were collected.Genetic testing led to the identification of gene mutations in 52 families (52/71, 73.2%). Forty-three families had PRRT2 mutations (43/71, 60.6%), including 40 families with frameshift mutations(hotspot mutations c. 649_650insC and c. 649delC were detected in 29 families and 6 families, respectively), one family with nonsense mutation, one family with a loss of a stop codon, and one family with a microdeletion of the gene.C.560_561insT and c. 679C>T were novel PRRT2 mutations.Five families had SCN2A mutations.All SCN2A mutations were missense mutations(c.668G>A, c.752T>C, c.1307T>C, c.4835C>G, c.1737C>G). Mutation c. 752T>C, c.1307T>C, c.4835C>G, and c. 1737C>G were novel mutations.Three families had KCNQ2 mutations.All KCNQ2 mutations were missense mutations(c.775G>A, c.237T>G, c.1510C>T). Mutation c. 237T>G and c. 1510C>T were novel mutations.One family had a novel GABRA6 mutation c. 523G>T.In 71 BFIE families, 16 families had members who showed paroxysmal kinesigenic dyskinesias(PKD)and subclassified as infantile convulsions with paroxysmal choreoathetosis syndrome(ICCA). Fifteen ICCA families were found having PRRT2 mutations (15/16, 93.8%). The remaining ICCA family was not detected with any pathogenic mutation. Conclusion There is high frequency of gene mutations in BFIE families.Mutations in KCNQ2, SCN2A, and PRRT2 are genetic causes of BFIE.PRRT2 is the main gene responsible for BFIE.GABRA6 mutation might be a new cause of BFIE. Key words: Benign familial infantile epilepsy; Infantile convulsions with paroxysmal choreoathetosis syndrome; KCNQ2 gene; SCN2A gene; PRRT2 gene; GABRA6 gene