Utility of genetic testing in children with leukodystrophy

Ayelet Zerem*, Stephanie Libzon, Liat Ben Sira, Hadas Meirson, Moran Hausman-Kedem, Noam Haviv, Keren Yosovich, Adi Mory, Hagit Baris Feldman, Dorit Lev, Tally Lerman-Sagie, Aviva Fattal-Valevski, Yael Hacohen, Daphna Marom

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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: 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: 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: 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.

Original languageEnglish
Pages (from-to)29-35
Number of pages7
JournalEuropean Journal of Paediatric Neurology
StatePublished - Jul 2023


  • Genetic leukoencephalopathy
  • Leukodystrophy
  • MRI
  • Next generation sequencing
  • White matter


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