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Sotos syndrome and haploinsufficiency of NSD1: clinical features of intragenic mutations and submicroscopic deletions
  1. T Nagai1,
  2. N Matsumoto2,
  3. N Kurotaki2,
  4. N Harada2,
  5. N Niikawa2,
  6. T Ogata3,
  7. K Imaizumi4,
  8. K Kurosawa4,
  9. T Kondoh5,
  10. H Ohashi6,
  11. M Tsukahara7,
  12. Y Makita8,
  13. T Sugimoto9,
  14. T Sonoda10,
  15. T Yokoyama11,
  16. K Uetake12,
  17. S Sakazume13,
  18. Y Fukushima13,
  19. K Naritomi14
  1. 1Department of Paediatrics, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Japan
  2. 2Department of Human Genetics, Nagasaki University School of Medicine, Nagasaki Japan
  3. 3Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japan
  4. 4Division of Medical Genetics, Kanagawa Children’s Medical Centre, Yokohama, Japan
  5. 5Department of Paediatrics, Nagasaki University School of Medicine, Nagasaki, Japan
  6. 6Division of Medical Genetics, Saitama Children’s Medical Centre, Iwatsuki, Japan
  7. 7Faculty of Health Science, Yamaguchi University School of Medicine, Ube, Japan
  8. 8Department of Paediatrics, Asahikawa Medical College, Asahikawa, Japan
  9. 9Department of Paediatrics, Kansai Medical University Otokoyama Hospital, Yawata, Japan
  10. 10Department of Paediatrics, Miyazaki Medical College, Miyazaki, Japan
  11. 11Department of Paediatrics, Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo, Japan
  12. 12Department of Paediatrics, Obihirokousei Hospital, Obihiro, Japan
  13. 13Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan
  14. 14Department of Medical Genetics, University of Ryukyu School of Medicine, Okinawa, Japan
  1. Correspondence to:
 Dr T Nagai, Department of Paediatrics, Koshigaya Hospital, Dokkyo University School of Medicine, 2-1-50 Minami-Koshigaya, Koshigaya-shi, Saitama 343-8555, Japan; 

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Sotos syndrome (MIM 117550) is a congenital developmental disorder characterised by overgrowth and advanced bone age in infancy to early childhood, mental retardation, and various minor anomalies such as macrocephaly, prominent forehead, hypertelorism, downward slanting palpebral fissures, large ears, high and narrow palate, and large hands and feet.1,2 It is also frequently associated with brain, cardiovascular, and urinary anomalies3–6 and is occasionally accompanied by malignant lesions such as Wilms tumour and hepatocarcinoma.7,8 This condition has been classified as an autosomal dominant disorder, because several familial cases consistent with dominant inheritance have been described previously.9 Thus, sporadic cases accounting for most of the Sotos syndrome patients are assumed to be the result of de novo dominant mutations.

We have recently shown that Sotos syndrome is caused by haploinsufficiency of the gene for NSD1 (nuclear receptor binding Su-var, enhancer of zeste, and trithorax domain protein 1).10NSD1 consists of 23 exons and encodes at least six functional domains possibly related to chromatin regulations (SET, PWWP-I, PWWP-II, PHD-I, PHD-II, and PHD-III), in addition to 10 putative nuclear localisation signals.11 It is expressed in several tissues including fetal/adult brain, kidney, skeletal muscle, spleen, and thymus11 and is likely to interact with nuclear receptors as a bifunctional transcriptional cofactor.12 In this paper, we report on clinical findings in Japanese patients with proven point mutations in NSD1 and those with submicroscopic deletions involving the entire NSD1 gene and discuss genotype-phenotype correlation.


This study consisted of five patients with heterozygous NSD1 point mutations and 21 patients with heterozygous submicroscopic deletions involving the entire NSD1 gene. The mutations were identified by direct sequencing of exons 2–23 and their flanking introns covering the whole coding region of NSD1,11 using genomic DNA extracted from peripheral leucocytes or …

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