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| Author(s): |
Helena Tadiello de Moraes
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2022-06-07 |
| Examining board members: |
Íscia Teresinha Lopes Cendes;
Ana Carolina Coan;
Antonia Paula Marques de Faria;
Kette Dualibi Ramos Valente;
Magda Lahorgue Nunes
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| Advisor: | Íscia Teresinha Lopes Cendes |
| Abstract | |
Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies, usually resistant to drug treatment and associated with delayed neuropsychomotor and cognitive development. With the advance of molecular genetic studies, mutations in many genes have been described in patients with DEEs; however, a significant proportion of these patients remains undiagnosed, assuming a monogenic model of inheritance. Thus, 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. Of the 275 patients with different types of DEEs that were initially ascertained, we obtained DNA samples from 239 of them. First, we used whole exome sequencing (WES) data from 234 of these patients and chromosomal microarray analysis (CMA) data from 236 of these patients to determine the molecular diagnostic yield of these techniques assuming a monogenic model. After individual analysis, the diagnostic yield was 38% for WES, 4.6% for CMA, and 38.9% for both techniques combined, representing a high diagnostic yield compared to the literature. Next, in the group of patients in whom a genetic cause could not be found, we used two exploratory approaches considering complex models of inheritance: logistic regression, which takes into account the presence of common genetic variants, which have allele frequency, MAF>0.01; and SKAT-O (optimized sequence kernel association test) which analyzes rare (MAF=0.01) and ultra-rare (MAF=0.0005) variants. We found a difference between the groups with and without a genetic diagnosis in the analysis of common variants. The latter showed a unique variant (rs9374755) with evidence of association (p = 0.000005) located in an RNA gene (LOC101927314). In the analysis with ultra-rare variants, we also observed a difference between the groups with and without genetic diagnosis, and for the latter we found seven candidate genes containing variants predisposing to the DEEs: ASPM (p=0.045517718); CREBBP (p=0.032086627); FASN (p=0.009504475); LAMC3 (p=0.001417445); RELN (p=0.017928247); RYR3 (p=0.047068168); and SPTAN1 (p=0.045613193). Our study showed that using traditional molecular diagnostic strategies, it was possible to find a monogenic cause in almost 40% of the patients with DEE investigated, with WES having the highest yield. The use of CMA was able to add almost five percentage points in the diagnostic yield and, therefore, should also be considered when investigating the genetic etiology of DEEs. Furthermore, we found evidence that at least part of the genetic effect present in the etiology of DEEs may follow a complex model of inheritance. Although it is not yet possible to apply these analyses to the routine genetic diagnosis of patients, our results indicate that a genetic etiology should be considered in patients with DEEs even in the absence of an identifiable monogenic cause. As the possibility of molecular diagnosis for genetic diseases of complex and multifactorial inheritance advances, we believe that the DEEs may benefit from this new knowledge and new methods of analyzing genetic data (AU) | |
| FAPESP's process: | 17/00648-1 - Investigating a polygenic effect in genomic data of patients with childhood epileptic encephalopathies (CEE) |
| Grantee: | Helena Tadiello de Moraes |
| Support Opportunities: | Scholarships in Brazil - Doctorate |