Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the 'beyond epilepsy' project.
Aminopeptidases
/ genetics
Child, Preschool
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
/ genetics
Early Diagnosis
Epilepsy
/ diagnosis
Female
Genetic Predisposition to Disease
/ genetics
Humans
Italy
Male
Methyl-CpG-Binding Protein 2
/ genetics
Neuronal Ceroid-Lipofuscinoses
/ diagnosis
Prospective Studies
Serine Proteases
/ genetics
Tripeptidyl-Peptidase 1
CLN2
Early diagnosis
Epilepsy
Next generation sequencing (NGS)
TPP1
Targeted re-sequencing
Journal
Italian journal of pediatrics
ISSN: 1824-7288
Titre abrégé: Ital J Pediatr
Pays: England
ID NLM: 101510759
Informations de publication
Date de publication:
06 Jul 2020
06 Jul 2020
Historique:
received:
28
04
2020
accepted:
01
07
2020
entrez:
8
7
2020
pubmed:
8
7
2020
medline:
16
6
2021
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 32631363
doi: 10.1186/s13052-020-00860-1
pii: 10.1186/s13052-020-00860-1
pmc: PMC7339579
doi:
Substances chimiques
MECP2 protein, human
0
Methyl-CpG-Binding Protein 2
0
Tripeptidyl-Peptidase 1
0
Serine Proteases
EC 3.4.-
Aminopeptidases
EC 3.4.11.-
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
EC 3.4.14.-
TPP1 protein, human
EC 3.4.14.9
Types de publication
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
92Références
Epilepsia. 2017 Aug;58(8):1380-1388
pubmed: 28632327
Pediatr Neurol. 2014 Jan;50(1):85-95
pubmed: 24120650
Drugs. 2017 Jul;77(11):1247-1249
pubmed: 28589525
J Med Genet. 2013 May;50(5):271-9
pubmed: 23468209
Bioessays. 2010 Jun;32(6):524-36
pubmed: 20486139
Genet Med. 2016 Sep;18(9):898-905
pubmed: 26795593
N Engl J Med. 2018 May 17;378(20):1898-1907
pubmed: 29688815
Nature. 2017 Oct 19;550(7676):345-353
pubmed: 29019985
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Epileptic Disord. 2016 Sep 1;18(S2):73-88
pubmed: 27629553
Pediatr Neurol. 2016 Nov;64:66-71
pubmed: 27726903
Epilepsia. 2018 Jun;59(6):1138-1147
pubmed: 29741288
Epilepsy Behav. 2014 Aug;37:241-8
pubmed: 25108116
Epilepsia. 2018 May;59(5):1062-1071
pubmed: 29655203
Brain Dev. 2001 Aug;23(5):306-11
pubmed: 11504601
J Child Neurol. 2016 Nov;31(13):1475-1482
pubmed: 27445018
Clin Genet. 1998 Sep;54(3):234-8
pubmed: 9788728
Neuropediatrics. 1997 Feb;28(1):6-8
pubmed: 9151309
Am J Hum Genet. 1999 Jun;64(6):1511-23
pubmed: 10330339
Neurology. 2007 Aug 7;69(6):521-35
pubmed: 17679671
Pharmacol Res. 2016 May;107:426-429
pubmed: 27080588
Mol Genet Metab. 2016 Sep;119(1-2):160-7
pubmed: 27553878
J Paediatr Child Health. 2020 Apr 24;:
pubmed: 32329550
Neurogenetics. 2020 Jan;21(1):1-18
pubmed: 31834528
J Biol Chem. 2009 Feb 6;284(6):3976-84
pubmed: 19038966
Epilepsia. 2010 Apr;51(4):655-70
pubmed: 20100225
Expert Rev Neurother. 2020 Mar;20(3):251-269
pubmed: 31941393
Biochim Biophys Acta. 2013 Nov;1832(11):1795-800
pubmed: 22959893
Lancet Child Adolesc Health. 2018 Aug;2(8):582-590
pubmed: 30119717
Neurosci Lett. 2018 Feb 22;667:4-9
pubmed: 28499889
Science. 1997 Sep 19;277(5333):1802-5
pubmed: 9295267
Brain Behav. 2019 May;9(5):e01250
pubmed: 30929312
Hum Mutat. 2019 Nov;40(11):1924-1938
pubmed: 31283065
Pediatr Neurol. 2017 Apr;69:102-112
pubmed: 28335910
J Child Neurol. 2013 Apr;28(4):470-8
pubmed: 22832778