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Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy


T2 hyperintensity of brain white matter lesions detected by magnetic resonance imaging (MRI) are characteristic of a heterogeneous group of diseases. Persistent T2 high intensity in combination with T1 iso- or high intensity of white matter in infants indicates a lack of normal myelination, that is, hypomyelination. However, the precise diagnosis of hypomyelinating leukodystrophy based solely on MRI findings can be difficult, especially in the early stage of the disease. We studied 26 patients who were diagnosed with hypomyelinating leukodystrophy according to MRI findings and clinical features to uncover their genetic etiology through chromosomal analyses, targeted gene analyses, and an array comparative genomic hybridization (aCGH) assay. Then, for the 17 patients with unexplained hypomyelination by traditional analyses, whole-exome sequencing (WES) was performed. The presumptive diagnoses were confirmed in 58 % of the enrolled patients (15/26) and involved 9 different genetic backgrounds. The most frequent backgrounds were 18q deletion syndrome and Pelizaeus–Merzbacher disease, with an incidence of 12 % (3/26) for both. The diagnostic rate of chromosomal analyses, targeted gene analyses, and aCGH was 31 % (8/26), and one patient was clinically diagnosed with Cockayne syndrome. Using WES, the following causative genes of hypomyelination were identified in six individuals (35 %, 6/17): TUBB4A, POLR3B, KCNT1, and MCOLN1, and some of those genes were pathogenic for not only hypomyelination but also dysmyelination or delayed myelination. Our findings suggested heterogeneous genetic backgrounds in patients with persistent white matter lesions. These data also indicate that WES may be a rapid and useful tool for identifying the underlying genetic causes of undiagnosed leukodystrophies.

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We thank all of the participants for their cooperation in this research and Ms. Y. Chiba and Ms. K. Ito for their technical assistance. We also acknowledge the support of the Biomedical Research Core of Tohoku University Graduate School of Medicine. This study was supported by JSPS KAKENHI Grant Number 25461533.

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Correspondence to Mitsugu Uematsu.

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Informed consent was obtained from all individual participants included in the study.


This study was funded by JSPS KAKENHI Grant Number 25461533.

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The authors have no conflicts of interest to declare.

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Arai-Ichinoi, N., Uematsu, M., Sato, R. et al. Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy. Hum Genet 135, 89–98 (2016). https://doi.org/10.1007/s00439-015-1617-7

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  • Magnetic Resonance Imaging Finding
  • Leukodystrophy
  • Compound Heterozygous Mutation
  • Cockayne Syndrome
  • Target Gene Analysis