Whole-exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late.
Adolescent
Adult
Aged
Arginine-tRNA Ligase
/ genetics
Child
Child, Preschool
Cohort Studies
Cytoskeletal Proteins
/ genetics
Delayed Diagnosis
Epilepsy
/ diagnosis
Exome
/ genetics
Female
Genetic Predisposition to Disease
Genetic Testing
Genomics
Humans
Infant
Male
Middle Aged
Neurodevelopmental Disorders
/ diagnosis
Exome Sequencing
/ methods
Young Adult
APC2
RARS2
WES
epilepsy
genetics
intellectual disability
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
15
06
2020
revised:
20
07
2020
accepted:
23
07
2020
pubmed:
30
7
2020
medline:
21
8
2021
entrez:
30
7
2020
Statut:
ppublish
Résumé
Developmental and epileptic encephalopathies (DEE) encompass rare, sporadic neurodevelopmental disorders and usually with pediatric onset. As these conditions are characterized by marked clinical and genetic heterogeneity, whole-exome sequencing (WES) represents the strategy of choice for the molecular diagnosis. While its usefulness is well established in pediatric DEE cohorts, our study is aimed at assessing the WES feasibility in adult DEE patients who experienced a diagnostic odyssey prior to the advent of this technique. We analyzed exomes from 71 unrelated adult DEE patients, consecutively recruited from an Italian cohort for the EPI25 Project. All patients underwent accurate clinical and electrophysiological characterization. An overwhelming percentage (90.1%) had already undergone negative genetic testing. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. WES disclosed 24 (likely) pathogenic variants among 18 patients in epilepsy-related genes with either autosomal dominant, recessive or X-linked inheritance. Ten of these were novel. We obtained a diagnostic yield of 25.3%, higher among patients with brain malformations, early-onset epilepsy and dysmorphisms. Despite a median diagnostic delay of 38.7 years, WES analysis provided the long-awaited diagnosis for 18 adult patients, which also had an impact on the clinical management of 50% of them.
Substances chimiques
APC2 protein, human
0
Cytoskeletal Proteins
0
Arginine-tRNA Ligase
EC 6.1.1.19
RARS2 protein, human
EC 6.1.1.19
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
477-485Subventions
Organisme : NHGRI NIH HHS
ID : 5U01HG009088-02
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008895
Pays : United States
Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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