Dados do Trabalho

Título

CNVs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis

Resumo

Introduction: Copy number variations (CNVs) are abnormal DNA segments of one kilobase (kb) or greater, present in a variable number of copies in the genome. To date, most studies of CNV in epilepsy were performed in patients with genetic generalized epilepsy (GGE) or associated comorbidities, especially intellectual disability. Objectives: We aimed to determine the presence and the distribution of CNVs in a large cohort of patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS) compared to patients with GGE and ethnic-matched controls. Methods: We evaluated 700 individuals (317 patients with MTLE+HS, 87 patients with GGE, and 296 controls). CNVs were accessed using the Affymetrix SNP-array 6.0 and recorded as the intersection of three different algorithms (copy number, parent-specific circular binary segmentation, and genome alteration detection analysis). Furthermore, we used quantitative real-time PCR to validate the CNVs classified as pathogenic or likely pathogenic. Results: Patients with MTLE+HS have more pathogenic and likely pathogenic CNVs than controls (p=0.013842, OD=4.128061, 95%CI:1.325254-17.057434), but not than patients with GGE (p=0.7959, OD=0.9294967, 95%CI:0.3167321-3.3201072). Overall, 5.4% (17/317) of the patients with MTLE+HS carry a pathogenic or likely pathogenic CNV compared to 5.7% (5/87) of the patients with GGE and 1.35% of controls (4/296). Most pathogenic and likely pathogenic chromosomal structural variants in patients with MTLE+HS were outside the so-called 'hot spots' for epilepsy, on chromosomes 15q11.2, 15q13.3, 16p13.11, 22q11.2, and Xp22.31. Rare CNVs encompassing one or more genes associated with epilepsy were identified in patients with MTLE+HS on chromosomes 2, 3, 4, 5, 7, 9, 13, and X. Remarkably, we found pathogenic or likely pathogenic CNVs on the X chromosome of 2.2% patients with MTLE+HS (7/317) and 2.3% patients with GGE (2/87). Noteworthy, most patients with MTLE+HS (70.6%,12/17) carrying a pathogenic/likely pathogenic CNV do not show any associated comorbidities. Only 17.6% (3/17) showed mild to severe intellectual disability, and 11.8% (2/17) showed psychiatric comorbidities. Conclusion: Our results suggest the need to incorporate the investigation of chromosomal structural abnormalities as part of the clinical assessment for patients with MTLE+HS independently of associate comorbidities.
Supported by: FAPESP and CEPID-BRAINN