PMID- 37267771 OWN - NLM STAT- MEDLINE DCOM- 20231020 LR - 20231020 IS - 1532-2130 (Electronic) IS - 1090-3798 (Linking) VI - 45 DP - 2023 Jul TI - Utility of genetic testing in children with leukodystrophy. PG - 29-35 LID - S1090-3798(23)00087-9 [pii] LID - 10.1016/j.ejpn.2023.05.008 [doi] AB - 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. CI - (c) 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. FAU - Zerem, Ayelet AU - Zerem A AD - Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: ayeletze@tlvmc.gov.il. FAU - Libzon, Stephanie AU - Libzon S AD - Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel; Magen Rare Disease Center, Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel. FAU - Ben Sira, Liat AU - Ben Sira L AD - Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Radiology, Department of Radiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. FAU - Meirson, Hadas AU - Meirson H AD - Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Hausman-Kedem, Moran AU - Hausman-Kedem M AD - Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Haviv, Noam AU - Haviv N AD - Statistical Advisor and Senior Lecturer, The Ashkelon Academic College, Israel. FAU - Yosovich, Keren AU - Yosovich K AD - Magen Rare Disease Center, Genetics Institute, Wolfson Medical Center, Holon, Israel. FAU - Mory, Adi AU - Mory A AD - Genetics Institute and Genomic Center, Tel Aviv Sourasky Medical Center, Israel. FAU - Baris Feldman, Hagit AU - Baris Feldman H AD - Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel; Genetics Institute and Genomic Center, Tel Aviv Sourasky Medical Center, Israel. FAU - Lev, Dorit AU - Lev D AD - Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel; Magen Rare Disease Center, Genetics Institute, Wolfson Medical Center, Holon, Israel. FAU - Lerman-Sagie, Tally AU - Lerman-Sagie T AD - Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel; Magen Rare Disease Center, Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel. FAU - Fattal-Valevski, Aviva AU - Fattal-Valevski A AD - Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Hacohen, Yael AU - Hacohen Y AD - Queen Square MS Centre, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom; Department of Neurology, Great Ormond Street Hospital for Children, London, United Kingdom. FAU - Marom, Daphna AU - Marom D AD - Sackler Faulty of Medicine, Tel Aviv University, Tel Aviv, Israel; Genetics Institute and Genomic Center, Tel Aviv Sourasky Medical Center, Israel. LA - eng PT - Journal Article DEP - 20230527 PL - England TA - Eur J Paediatr Neurol JT - European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society JID - 9715169 SB - IM CIN - Eur J Paediatr Neurol. 2023 Jul;45:A2-A3. PMID: 37414653 MH - Child, Preschool MH - Female MH - Humans MH - Infant MH - Male MH - Exome Sequencing MH - *Genetic Testing MH - High-Throughput Nucleotide Sequencing MH - Retrospective Studies MH - White Matter/pathology MH - *Hereditary Central Nervous System Demyelinating Diseases/diagnosis/genetics/pathology/physiopathology MH - Child MH - Adolescent MH - Jews/genetics MH - Magnetic Resonance Imaging MH - Founder Effect OTO - NOTNLM OT - Genetic leukoencephalopathy OT - Leukodystrophy OT - MRI OT - Next generation sequencing OT - White matter COIS- Declaration of competing interest We declare no competing interests. EDAT- 2023/06/03 11:42 MHDA- 2023/07/24 06:42 CRDT- 2023/06/02 18:05 PHST- 2023/02/04 00:00 [received] PHST- 2023/05/22 00:00 [accepted] PHST- 2023/07/24 06:42 [medline] PHST- 2023/06/03 11:42 [pubmed] PHST- 2023/06/02 18:05 [entrez] AID - S1090-3798(23)00087-9 [pii] AID - 10.1016/j.ejpn.2023.05.008 [doi] PST - ppublish SO - Eur J Paediatr Neurol. 2023 Jul;45:29-35. doi: 10.1016/j.ejpn.2023.05.008. Epub 2023 May 27.