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Identification of eight novel NSD1 mutations in Sotos syndrome
  1. J Kamimura1,2,3,
  2. Y Endo1,
  3. N Kurotaki1,
  4. A Kinoshita1,3,
  5. N Miyake1,3,
  6. O Shimokawa4,
  7. N Harada1,3,4,
  8. R Visser1,6,7,
  9. H Ohashi8,
  10. K Miyakawa9,
  11. J Gerritsen10,
  12. A M Innes10,
  13. L Lagace11,
  14. M Frydman12,
  15. N Okamoto13,
  16. R Puttinger14,
  17. S Raskin15,
  18. B Resic16,
  19. V Culic16,
  20. K Yoshiura1,3,
  21. T Ohta3,5,
  22. T Kishino3,5,
  23. M Ishikawa2,
  24. N Niikawa1,3,
  25. N Matsumoto1,3
  1. 1Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  2. 2Department of Obstetrics and Gynecology, Asahikawa Medical College, Asahikawa, Japan
  3. 3CREST, Japan Science and Technology Corporation, Kawaguchi, Japan
  4. 4Kyushu Medical Science Nagasaki Laboratory, Nagasaki, Japan
  5. 5Division of Functional Genomics, Research Center for Frontier Life Sciences, Nagasaki University, Nagasaki, Japan
  6. 6International Consortium for Medical Care of Hibakusha and Radiation Life Science, The 21st Century COE (Center of Excellence), Nagasaki, Japan
  7. 7Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
  8. 8Division of Medical Genetics, Saitama Children’s Medical Center, Saitama, Japan
  9. 9Division of Pediatrics, Niigata City General Hospital, Niigata, Japan
  10. 10Department of Medical Genetics, University of Calgary, Calgary, Canada
  11. 11East Central Health, Alberta, Canada
  12. 12Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Aviv University, Ramat Gan, Israel
  13. 13Department of Planning and Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan
  14. 14Klinsche Genetik, St. Johanns-Spital, Salzburg, Austria
  15. 15Laboratorio Genetika, Curitiba Parana, Brazil
  16. 16Clinical Hospital Split, Pediatrics Clinic, Department of Developmental Neurology and Medical Genetics, Spinciceva, Croatia
  1. Correspondence to:
 Dr N Matsumoto
 Department of Human Genetics, Nagasaki University School of Medicine, Sakamoto 1-12-4, Nagasaki 852-8523, Japan;

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Sotos syndrome or cerebral gigantism (SoS, OMIM #117550) is a well-known disorder characterised by overgrowth with advanced bone age, craniofacial anomalies, developmental delay, and occasional seizures.1,2 A typical face has a large head circumference, frontal bossing with high anterior hairline, down slanting of palpebral fissures, flat nasal bridge, and prominent jaw.3 The hands and feet are usually large. Height and weight tends to normalise in adulthood.4 EEG abnormalities, hypotonia, strabismus, congenital heart defects, kyphoscoliosis, and cancer have also been noted.3,5–10 Since the original report in 1964,1 more than 300 affected cases have been reported. Most cases are sporadic, while several familial cases have been described, suggesting that SoS is an autosomal dominant disorder.8,11–17

We have previously isolated the nuclear receptor SET domain containing gene 1 (NSD1) from the 5q35 translocation breakpoint in a Japanese SoS patient with t(5;8)(q35; q24.1).18,19NSD1 encodes 2696 amino acids (GenBank accession no. AF395588), and the gene has several putative functional domains, such as NID−L, NID+L, SET, SAC, PWWP-I, PWWWP-II, PHD-I, PHD-II, and PHD-III, suggesting that the NSD1 protein may be associated with chromatin mediated transcriptional regulation.19–24 In 42 Japanese sporadic cases of SoS, we identified 20 submicroscopic deletions including the entire NSD1 gene and four point mutations, the data indicating that SoS is caused by haploinsufficiency of NSD1.25 Recently, a UK group reported 29 novel NSD1 point mutations and only three microdeletions in 37 typical SoS and 13 SoS-like patients, and suggested that NSD1 intragenic mutations instead of microdeletions were the major cause of SoS.26

In this study, we validated the spectrum of NSD1 intragenic mutations among 30 newly collected SoS patients.


The subjects studied included 13 Japanese and 17 non-Japanese patients with …

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