Utility of genetic testing in children with leukodystrophy

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.