Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features

Yuriko Yoneda, Hirotomo Saitsu, Mayumi Touyama, Yoshio Makita, Akie Miyamoto, Keisuke Hamada, Naohiro Kurotaki, Hiroaki Tomita, Kiyomi Nishiyama, Yoshinori Tsurusaki, Hiroshi Doi, Noriko Miyake, Kazuhiro Ogata, Kenji Naritomi, Naomichi Matsumoto

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)


Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T>C (p.Leu60Pro) mutation occurred de novo and the c.362G>C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/ dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.

Original languageEnglish
Pages (from-to)207-211
Number of pages5
JournalJournal of Human Genetics
Issue number3
Publication statusPublished - 2012 Mar


  • DNA-binding/dimerization domain
  • NFIX
  • Sotos syndrome
  • missense mutation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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