Dados do Trabalho

Título

Genetic characterization of a large cohort of patients with developmental and epileptic encephalopathies from Latin America

Introdução

Developmental and epileptic encephalopathies (DEE) are a group of severe epilepsies, usually resistant to clinical treatment and associated with delayed neuropsychomotor and cognitive development. With the advancement of molecular studies in recent years, new mutations associated with DEE have been described. However, a significant number of patients remain without identified causative genetic variants.

Objetivo

The main objective of this work was to apply new analytical paradigms to identify and investigate genetic variants in a large cohort
of patients with DEEs from Latin America.

Método

First, we performed whole-exome sequencing (WES) and chromosomal microarray analysis (CMA) to determine the molecular diagnostic yield in 239 patients from several different countries in Latin America, assuming a monogenic model of inheritance. Second, we used the group of patients in whom a monogenic cause for the disease could not be found to test for complex inheritance patterns using logistic regression (LR) and SKAT-O.

Resultados

WES allowed the genetic diagnosis in 38% of 234 patients, while CMA achieved the diagnosis in 4.6% of 220 patients. In the LR analysis using common variants (n=142 patients), we found one SNP (rs9374755) possible associated with the disease. Using SKAT-O analysis in the same group of patients, we identified significant associations with a set of ultra-rare variants present in ten genes: LAMC3, PTPN23, TBCD, FASN, RELN, CREBBP, ASPM, SPTAN1, RYR3, and HERC.

Conclusão

Using both WES and CMA, it was possible to confirm the genetic diagnoses of 38.9% of the patients with DEE studied. WES alone achieved a higher diagnostic yield than CMA alone (38% x 4.6%); however, using both methods increased the proportion of patients with positive findings. Furthermore, the complex inheritance analyses identified possible association with a common SNP and ultra-rare variants in 10 candidate genes for epilepsy, thus indicating that a complex inheritance model could also be present in patients with DEE. Noteworthy, this is the first large and comprehensive genetic study of patients with DEE in Latin America.

Palavras-chave

DEE, epilepsy, genetic variation, Latin America