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Somatic mosaicism containing double mutations in PTCH1 revealed by generation of induced pluripotent stem cells from nevoid basal cell carcinoma syndrome
  1. Yu Ikemoto1,2,
  2. Yoshinaga Takayama1,3,
  3. Katsunori Fujii4,
  4. Mokuri Masuda1,
  5. Chise Kato1,
  6. Hiromi Hatsuse3,
  7. Kazuko Fujitani5,
  8. Kazuaki Nagao1,3,
  9. Kohzoh Kameyama1,3,
  10. Hajime Ikehara2,4,
  11. Masashi Toyoda6,
  12. Akihiro Umezawa2,
  13. Toshiyuki Miyashita1,3
  1. 1 Department of Molecular Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan
  2. 2 Center for Regenerative Medicine, National Research Institute for Child Health and Development, Tokyo, Japan
  3. 3 Department of Molecular Genetics, Kitasato University School of Medicine, Sagamihara, Japan
  4. 4 Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan
  5. 5 Gene Analysis Center, Kitasato University School of Medicine, Sagamihara, Japan
  6. 6 Research Team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
  1. Correspondence to Dr Toshiyuki Miyashita, Department of Molecular Genetics, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara 252-0374, Japan; tmiyashi{at}


Background Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterised by developmental defects and tumorigenesis, such as medulloblastomas and basal cell carcinomas, caused by mutations of the patched-1 (PTCH1) gene. In this article, we seek to demonstrate a mosaicism containing double mutations in PTCH1 in an individual with NBCCS.

Methods and results A de novo germline mutation of PTCH1 (c.272delG) was detected in a 31-year-old woman with NBCCS. Gene analysis of two out of four induced pluripotent stem cell (iPSC) clones established from the patient unexpectedly revealed an additional mutation, c.274delT. Deep sequencing confirmed a low-prevalence somatic mutation (5.5%–15.6% depending on the tissue) identical to the one found in iPSC clones.

Conclusions This is the first case of mosaicism unequivocally demonstrated in NBCCS. Furthermore, the mosaicism is unique in that the patient carries one normal and two mutant alleles. Because these mutations are located in close proximity, reversion error is likely to be involved in this event rather than a spontaneous mutation. In addition, this study indicates that gene analysis of iPSC clones can contribute to the detection of mosaicism containing a minor population carrying a second mutation.

  • Mosaicism AND two mutations
  • PTCH1
  • nevoid basal cell carcinoma syndrome
  • deep sequencing

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  • Contributors YI, HI, MT and AU established and characterised iPS clones. HH, KN and CK performed the Sanger sequencing. YT, MM and KF performed the HaloPlexHS capture and next-generation sequencing. KF conducted sample acquisition, collected clinical information and associated administration work. KK collected references and edited the manuscript. AU and TM created the design of the study and edited the manuscript. All authors read and approved the final manuscript.

  • Funding This study was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan Grant-in-Aid for Scientific Research (KAKENHI) 26461530 (to T. M.), 15K19041 (to K. N.) and 16K09960 (to K. Fujii), and by the Research Project for Practical Applications of Regenerative Medicine from the Japan Agency for Medical Research and Development, AMED (to A.U.) and by a grant from Kitasato University Graduate School of Medical Sciences (Integrative Research Program 201572016) (to T. M.).

  • Competing interests None declared.

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

  • Correction notice This article has been updated since it published Online First. The funding statement was incorrectly labelled as ‘Ethics Approval’ statement. This has been corrected in this new version.