AIM: Developmental and epileptic encephalopathies (DEEs) are a group of 
devastating disorders caused by epileptic activity, resulting in deterioration 
in developmental, cognitive, and motor functions. The number of genes identified 
as being responsible for DEEs has been increasing rapidly. However, despite a 
comprehensive molecular analysis, a molecular diagnosis can only be established 
in 50% of cases. The aim of this project is to use whole exome sequencing (WES) 
to determine the molecular etiology of DEEs in undiagnosed patients with a 
pedigree suggestive of an autosomal recessive single gene disease.
METHODS: Three DEE families, having either consanguineous parents of an affected 
individual and/or having more than one affected offspring, were enrolled in the 
project. Prior to this project, the families had been evaluated using a 
next-generation sequencing panel including 16 DEE genes in a previous study; 
however, no molecular diagnosis could be established. In five cases from the 
three selected DEEs families in our study, the genetic etiology was investigated 
using WES.
RESULTS: All patients in the study group had infantile onset epileptic seizures; 
however, semiologies varied. All patients presented with severe developmental 
delay. WES revealed biallelic disease causing mutations in DENDD5A, GRN, and 
TBCD genes in family 1, family 2, and family 3, respectively. In each family, 
the identified variants associated with the disease were segregated. Reverse 
phenotyping supported the molecular analysis.
CONCLUSION: This study provided a valuable contribution to the 
genotype-phenotype relationship by determining rare epilepsy syndromes in 
undiagnosed patients previously. WES is a useful diagnostic alternative, 
particularly in consanguineous families.