Utility of genetic testing in children with leukodystrophy.
Child, Preschool
Female
Humans
Infant
Male
Exome Sequencing
Genetic Testing
High-Throughput Nucleotide Sequencing
Retrospective Studies
White Matter
/ pathology
Hereditary Central Nervous System Demyelinating Diseases
/ diagnosis
Child
Adolescent
Jews
/ genetics
Magnetic Resonance Imaging
Founder Effect
Genetic leukoencephalopathy
Leukodystrophy
MRI
Next generation sequencing
White matter
Journal
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society
ISSN: 1532-2130
Titre abrégé: Eur J Paediatr Neurol
Pays: England
ID NLM: 9715169
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
04
02
2023
accepted:
22
05
2023
medline:
24
7
2023
pubmed:
3
6
2023
entrez:
2
6
2023
Statut:
ppublish
Résumé
Leukodystrophies are monogenic disorders primarily affecting the white matter. We aimed to evaluate the utility of genetic testing and time-to-diagnosis in a retrospective cohort of children with suspected leukodystrophy. Medical records of patients who attended the leukodystrophy clinic at the Dana-Dwek Children's Hospital between June 2019 and December 2021 were retrieved. Clinical, molecular, and neuroimaging data were reviewed, and the diagnostic yield was compared across genetic tests. Sixty-seven patients (Female/Male ratio 35/32) were included. Median age at symptom onset was 9 months (interquartile range (IQR) 3-18 months), and median length of follow-up was 4.75 years (IQR 3-8.5). Time from symptom onset to a confirmed genetic diagnosis was 15months (IQR 11-30). Pathogenic variants were identified in 60/67 (89.6%) patients; classic leukodystrophy (55/67, 82.1%), leukodystrophy mimics (5/67, 7.5%). Seven patients (10.4%) remained undiagnosed. Exome sequencing showed the highest diagnostic yield (34/41, 82.9%), followed by single-gene sequencing (13/24, 54%), targeted panels (3/9, 33.3%) and chromosomal microarray (2/25, 8%). Familial pathogenic variant testing confirmed the diagnosis in 7/7 patients. A comparison between patients who presented before (n = 31) and after (n = 21) next-generation sequencing (NGS) became clinically available in Israel revealed that the time-to-diagnosis was shorter in the latter group with a median of 12months (IQR 3.5-18.5) vs. a median of 19 months (IQR 13-51) (p = 0.005). NGS carries the highest diagnostic yield in children with suspected leukodystrophy. Access to advanced sequencing technologies accelerates speed to diagnosis, which is increasingly crucial as targeted treatments become available.
Sections du résumé
BACKGROUND
BACKGROUND
Leukodystrophies are monogenic disorders primarily affecting the white matter. We aimed to evaluate the utility of genetic testing and time-to-diagnosis in a retrospective cohort of children with suspected leukodystrophy.
METHODS
METHODS
Medical records of patients who attended the leukodystrophy clinic at the Dana-Dwek Children's Hospital between June 2019 and December 2021 were retrieved. Clinical, molecular, and neuroimaging data were reviewed, and the diagnostic yield was compared across genetic tests.
RESULTS
RESULTS
Sixty-seven patients (Female/Male ratio 35/32) were included. Median age at symptom onset was 9 months (interquartile range (IQR) 3-18 months), and median length of follow-up was 4.75 years (IQR 3-8.5). Time from symptom onset to a confirmed genetic diagnosis was 15months (IQR 11-30). Pathogenic variants were identified in 60/67 (89.6%) patients; classic leukodystrophy (55/67, 82.1%), leukodystrophy mimics (5/67, 7.5%). Seven patients (10.4%) remained undiagnosed. Exome sequencing showed the highest diagnostic yield (34/41, 82.9%), followed by single-gene sequencing (13/24, 54%), targeted panels (3/9, 33.3%) and chromosomal microarray (2/25, 8%). Familial pathogenic variant testing confirmed the diagnosis in 7/7 patients. A comparison between patients who presented before (n = 31) and after (n = 21) next-generation sequencing (NGS) became clinically available in Israel revealed that the time-to-diagnosis was shorter in the latter group with a median of 12months (IQR 3.5-18.5) vs. a median of 19 months (IQR 13-51) (p = 0.005).
CONCLUSIONS
CONCLUSIONS
NGS carries the highest diagnostic yield in children with suspected leukodystrophy. Access to advanced sequencing technologies accelerates speed to diagnosis, which is increasingly crucial as targeted treatments become available.
Identifiants
pubmed: 37267771
pii: S1090-3798(23)00087-9
doi: 10.1016/j.ejpn.2023.05.008
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
29-35Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
Déclaration de conflit d'intérêts
Declaration of competing interest We declare no competing interests.