Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the 'beyond epilepsy' project.

Autor: Amadori E; Pediatric Neurology and Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, 16147, Genoa, Italy.; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy., Scala M; Pediatric Neurology and Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, 16147, Genoa, Italy.; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy., Cereda GS; Pediatric Neurology and Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, 16147, Genoa, Italy., Vari MS; Pediatric Neurology and Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, 16147, Genoa, Italy., Marchese F; Pediatric Neurology and Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, 16147, Genoa, Italy., Di Pisa V; Child Neurology and Psychiatry Unit, Department of Medical and Surgical Sciences (DIMEC), S. Orsola Hospital, University of Bologna, Bologna, Italy., Mancardi MM; Child Neuropsychiatry Unit, Epilepsy Centre, Department of Clinical and Surgical Neurosciences and Rehabilitation, IRCSS 'G. Gaslini' Institute, Genoa, Italy., Giacomini T; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.; Child Neuropsychiatry Unit, Epilepsy Centre, Department of Clinical and Surgical Neurosciences and Rehabilitation, IRCSS 'G. Gaslini' Institute, Genoa, Italy., Siri L; Child Neuropsychiatry Unit, IRCSS 'G. Gaslini' Institute, Genoa, Italy., Vercellino F; Department of Child Neurology and Psychiatry, Cesare Arrigo Hospital, Alessandria, Italy., Serino D; Department of Paediatric Neurology, Royal Aberdeen Children's Hospital, Aberdeen, UK.; Child Neurology and Psychiatry Unit, ASL CN1, Cuneo, Italy., Orsini A; Pediatric Neurology, Pediatric Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy., Bonuccelli A; Pediatric Neurology, Pediatric Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy., Bagnasco I; Division of Child Neuropsychiatry, Martini Hospital, via Tofane 71, 10141, Torino, Italy., Papa A; Department of Child Neuropsychiatry, AOU Maggiore della Carita, Novara, Italy., Minetti C; Pediatric Neurology and Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, 16147, Genoa, Italy.; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy., Cordelli DM; Child Neurology and Psychiatry Unit, Department of Medical and Surgical Sciences (DIMEC), S. Orsola Hospital, University of Bologna, Bologna, Italy., Striano P; Pediatric Neurology and Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, 16147, Genoa, Italy. strianop@gmail.com.; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy. strianop@gmail.com.
Jazyk: angličtina
Zdroj: Italian journal of pediatrics [Ital J Pediatr] 2020 Jul 06; Vol. 46 (1), pp. 92. Date of Electronic Publication: 2020 Jul 06.
DOI: 10.1186/s13052-020-00860-1
Abstrakt: Background: Childhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome. Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative condition caused by biallelic TPP1 variants. This disorder presents with subtle and relatively non-specific symptoms, mimicking those observed in more common paediatric epilepsies and followed by rapid psychomotor deterioration and drug-resistant epilepsy. A prompt diagnosis is essential to adopt appropriate treatment and disease management strategies.
Methods: This is a prospective, multicentre study on the efficiency of targeted re-sequencing in the early identification of the genetic causes of childhood epilepsy, with particular regard to CLN2. After phenotypic characterization, a 283-gene Next Generation Sequencing panel was performed in 21 Italian children with neurodevelopmental abnormalities, aged between 24 and 60 months, experiencing first unprovoked seizure after 2 years of age.
Results: The average age at enrolment was 39.9 months, with a mean age at seizure onset of 30.9 months and a mean time interval between seizure onset and targeted resequencing of 9 months. Genetic confirmation was achieved in 4 out of 21 patients, with a diagnostic yield of 19%. In one case, the homozygous splice acceptor variant c.509-1G > C in TPP1 was identified, leading to a CLN2 diagnosis. Three pathogenic variants in MECP2 were also detected in three patients, including the frameshift variant c.1157_1186delinsA (p.Leu386Hisfs*9) in a girl with negative single gene sequencing. Variants of unknown significance (VUS) were found in 11 out of 21 (52.4%) individuals, whereas no clinically significant variants were observed in the remaining 6 subjects.
Conclusions: Our findings support the efficacy of target re-sequencing in the identification of the genetic causes of childhood epilepsy and suggest that this technique might prove successful in the early detection of CLN2 as well as other neurodevelopmental conditions.
Databáze: MEDLINE
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