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Rapid detection of a mutation causing X-linked leucoencephalopathy by exome sequencing
  1. Yoshinori Tsurusaki1,
  2. Hitoshi Osaka2,
  3. Haruka Hamanoue1,
  4. Hiroko Shimbo2,
  5. Megumi Tsuji2,
  6. Hiroshi Doi1,
  7. Hirotomo Saitsu1,
  8. Naomichi Matsumoto1,
  9. Noriko Miyake1
  1. 1Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  2. 2Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan
  1. Correspondence to Dr Noriko Miyake, Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; nmiyake{at}


Background Conventional PCR-based direct sequencing of candidate genes for a family with X-linked leucoencephalopathy with unknown aetiology failed to identify any causative mutations.

Objective To carry out exome sequencing of entire transcripts of the whole X chromosome to investigate a family with X linked leucoencephalopathy.

Methods and results Next-generation sequencing of all the transcripts of the X chromosome, after liquid-based genome partitioning, was performed on one of the two affected male subjects (the proband) and an unaffected male subject (his brother). A nonsense mutation in MCT8 (c.1102A→T (p.R368X)) was identified in the proband. Subsequent PCR-based direct sequencing of other family members confirmed the presence of this mutation, hemizygous in the other affected brother and heterozygous in the proband's mother and maternal grandmother. MCT8 mutations usually cause abnormal thyroid function in addition to neurological abnormalities, but this proband had normal thyroid function.

Conclusion Single-lane exome next-generation sequencing is sufficient to fully analyse all the transcripts of the X chromosome. This method is particularly suitable for mutation screening of X-linked recessive disorders and can avoid biases in candidate gene choice.

  • Next-generation sequencing (NGS)
  • X linked leucoencephalopathy
  • exome sequencing
  • MCT8
  • genetics
  • neurology

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  • Funding This work was supported by research grants from the Ministry of Health, Labour and Welfare (to HO, HSa, NMa and NMi), a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (NMa), a grant-in-aid for young scientists from the Japan Society for the Promotion of Science (HSa), a grant from the 2010 Strategic Research Promotion of Yokohama City University (NMa), research grants from the Japan Epilepsy Research Foundation (HSa) and a research grant from the Naito Foundation (NMa). The study sponsors had no role in the study design; in the collection, analysis, and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the institutional review board of Kanagawa Children's Medical Center and Yokohama City University School of Medicine.

  • Provenance and peer review Not commissioned; externally peer reviewed.