Abstract: Objective To summarize the phenotypes and identify gene mutation in families with generalized epilepsy with febrile seizures plus (GEFS+). Methods Genomic DNA was extracted from peripheral blood lymphocytes of the proband and available members in the GEFS+ families. The phenotypes of the affected members were analyzed. Illumina HiSeq 2000 series of high throughput sequencing screening for all epilepsy related genes in children. the gene locus of the mutant gene was verified by other members of the family when the suspected mutant gene was found. Results Nine members affected in three families. Their phenotypes included 3 cases of febrile seizures (FS), 3 cases of febrile seizures plus (FS+), 2 cases of afebrile generalized onic-clonic seizures (AGTCS). One case of childhood absence epilepsy with FS+. The family was found with SCN5A and ABCC6 mutations, including exon 28 mutations (c.2592G>A) of SCN5A and exon 10 Shear site variation(c.1338+1G>A) of ABCC6. The unaffected grandfather had the mutation of SCN5A gene, and the affected grandmother had the mutation of ABCC6 gene. Conclusion One unreported suspected pathogenic gene, ABCC6, is found in this study, and we did not find the gene mutation of which had been reported. GEFS+ is a polygenic hereditary disease. Genetic mechanism is complex in GEFS+ families that needs further research.