Diagnostic Yield and Copy Number Variants Findings in 220 Adult Patients with Developmental and Epileptic Encephalopathies
Abstract number :
1.123
Submission category :
12. Genetics / 12A. Human Studies
Year :
2024
Submission ID :
897
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Laura Licchetta, Md PhD – IRCCS, Istituto delle Scienze Neurologiche di Bologna, Full Member of the European Reference Network for Rare and Complex Epilepsies
Tania Giangregorio, PhD – Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Raffaella Minardi, PhD – IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of European Reference Network EpiCARE, Bologna, Italy
Elisa Mannini, MD – Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
Giulia Bruschi, MD – IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of European Reference Network EpiCARE, Bologna, Italy
Lorenzo Serra, BS – Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Italy
Carlotta Stipa, MD – IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of European Reference Network EpiCARE, Bologna, Italy
Barbara Mostacci, MD, PhD – IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of European Reference Network EpiCARE, Bologna, Italy
Tommaso Pippucci, PhD – Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Pamela Magini, PhD – Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Francesca Bisulli, MD, PhD – IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of European Reference Network EpiCARE, Bologna, Italy
Rationale: Most monogenic Developmental and epileptic encephalopathies (DEE) are caused by pathogenic de novo single-nucleotide variants in genes, each contributing to a limited proportion of cases1. Thus, WES is considered the most convenient approach for DEE2, although chromosomal microarray (CMA) for copy number variants (CNVs) detection would be the first-tier genetic test for patients with epilepsy, intellectual disability and/or dysmorphisms, according to diagnostic algorithms3.
Most of the studies on CNVs focused on paediatric cohorts4, whereas data on adult patients – representing the so-called “lost generation” - are scant. We investigate the role of CNVs in the etiology of DEE in an adult cohort.
Methods: We selected all patients with undiagnosed DEE referred to the tertiary epilepsy center of our Institute. All patients underwent an accurate electro-clinical assessment. CNV identification was performed by (i) the Agilent Technologies array-CGH 8x60K platform and Cytogenomics software (Agilent technologies) or (ii) SNP-array from Epi25 data using PennCNV for variant calling and AnnotSV software for variant annotation.
Results: We included 220 unrelated DEE patients (M/F:104/116) who underwent array-CGH or SNP-array as adults. We identified causative CNVs in 18 patients (8.2%), 8 of whom de novo (44.4%): del1p36.33-p36.23, dup1q21.1q21.2, del2p16.3, mosaic del2q23, del2q23.3q24.2, del2q37.3, del3p14.2p14.1, del3q29, del6q27, del13q13.2q13.3, del15q11.2q13.1 compatible with Angelman syndrome, dup15q11.2q13, 15q13.2q13.3x3+15q11.2q13.2x4 compatible with an inv-dup (15) syndrome, dup16p13.1, del 17q21.31, del 19q12-q13.11, del 22q11.2, del 22q13.33.
The mean age at diagnosis was 32.4±13 years.
Of the remaining, 24 (10.9%) had VUS, 178 (80.9%) were negative.
Conclusions: The diagnostic yield of CNV analysis in our adult DEE cohort was 8.2%, aligning with literature data on pediatric cohorts. This analysis allowed for the establishment of a genetic diagnosis and ended the diagnostic odyssey, despite the diagnostic delay. Although WES is now considered the first approach to reduce diagnostic costs and time, incorporating CNV analysis is recommended in the diagnostic workflow for adult patients with DEE as well.
Funding: Epi25 consortium
Genetics