Sotos Syndrome

Abstract

Sotos syndrome (OMIM #117550) is a childhood overgrowth syndrome with distinctive craniofacial features and mental retardation. Sotos syndrome is caused by haploinsufficiency of the nuclear receptor SET domain containing protein 1 gene (NSD1) located at 5q35.2‐q35.3. A wide variety of NSD1 aberrations have been found: microdeletions, intragenic deletions and missense and truncation mutations. Through in‐depth analyses of microdeletions, low copy repeat (LCR) or Alu‐mediated rearrangements were demonstrated to be major mechanisms for de novo deletions. Therefore, Sotos syndrome is now considered as a genomic disorder. NSD1 is a protein with histone methyltransferase activity and nuclear receptor‐binding capability, both related to transcriptional controls. As pathophysiology regarding abnormalities of NSD1 protein remains unknown, further functional studies are necessary.

Key concepts

  • Haploinsufficiency of NSD1 causes Sotos syndrome.

  • Sotos syndrome is a genomic disorder.

  • Microdeletion involving NSD1 occurs through nonallelic homologous recombination mediated by low copy repeats or Alu elements.

  • NSD1 has specific histone methyltransferase activity.

Keywords: overgrowth syndrome; NSD1; microdeletion; point mutation; histone methyltransferase activity

Figure 1.

Facial appearance of Sotos syndrome. A Japanese girl carrying a whole NSD1 gene microdeletion at the age of two months (left) and at three years (right). Photographs were originally provided by Dr. Nobuhiko Okamoto at the Department of Planning and Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan, and reproduced by permission of Oxford University Press from Visser R and Matsumoto N (in press) NSD1 and Sotos syndrome. In: Inborn Errors of Development, 2nd edn, chap. 113.

Figure 2.

Low copy repeats associated with Sotos syndrome. Proximal low copy repeat (PLCR) contains eight different blocks (A–H) and distal LCR (DLCR) possesses nine blocks (A–H including two Bs). The most common microdeletion between PLCR‐B and DLCR‐2B is presented.

Figure 3.

NSD1 and its functional domains. SET, su(var) 3‐9, enhancer of zeste, trithorax domain; SAC, SET‐associated Cys‐rich domain; PWWP, proline‐tryptophan‐tryptophan‐proline domain; PHD, zinc‐finger plant homeodomain and NID, nuclear receptor interaction domain.

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References

Aasland R, Gibson TJ and Stewart AF (1995) The PHD finger: implications for chromatin‐mediated transcriptional regulation. Trends in Biochemical Science 20: 56–59.

Adhvaryu KK, Morris SA, Strahl BD et al. (2005) Methylation of histone H3 lysine 36 is required for normal development in Neurospora crassa. Eukaryot Cell 4: 1455–1464.

Angrand PO, Apiou F, Stewart AF et al. (2001) NSD3, a new SET domain‐containing gene, maps to 8p12 and is amplified in human breast cancer cell lines. Genomics 74: 79–88.

Baujat G, Rio M, Rossignol S et al. (2004) Paradoxical NSD1 mutations in Beckwith‐Wiedemann syndrome and 11p15 anomalies in Sotos syndrome. American Journal Human Genetics 74: 715–720.

Cecconi M, Forzano F, Milani D et al. (2005) Mutation analysis of the NSD1 gene in a group of 59 patients with congenital overgrowth. American Journal of Medical Genetics A 134: 247–253.

Cole TR and Hughes HE (1994) Sotos syndrome: a study of the diagnostic criteria and natural history. Journal Medical Genetics 31: 20–32.

De Boer L, Van Duyvenvoorde HA, Willemstein‐Van Hove EC et al. (2004) Mutations in the NSD1 gene in patients with Sotos syndrome associate with endocrine and paracrine alterations in the IGF system. European Journal of Endocrinology 151: 333–341.

Douglas J, Hanks S, Temple IK et al. (2003) NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. American Journal of Human Genetics 72: 132–143.

Douglas J, Tatton‐Brown K, Coleman K et al. (2005) Partial NSD1 deletions cause 5% of Sotos syndrome and are readily identifiable by multiplex ligation dependent probe amplification. Journal of Medical Genetics 42: e56.

Giunta C, Randolph A, Al‐Gazali LI et al. (2005) Nevo syndrome is allelic to the kyphoscoliotic type of the Ehlers‐Danlos syndrome (EDS VIA). American Journal of Medical Genetics A 133A: 158–164.

Huang N, vom Baur E, Garnier JM et al. (1998) Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators. EMBO Journal 17: 3398–3412.

Jaju RJ, Fidler C, Haas OA et al. (2001) A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood 98: 1264–1267.

Kanemoto N, Kanemoto K, Nishimura G et al. (2006) Nevo syndrome with an NSD1 deletion: a variant of Sotos syndrome? American Journal of Medical Genetic A 140: 70–73.

Klose RJ, Yamane K, Bae Y et al. (2006) The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442: 312–316.

Kouzarides T (2002) Histone methylation in transcriptional control. Current Opinion in Genetic & Development 12: 198–209.

Kurotaki N, Harada N, Shimokawa O et al. (2003) Fifty microdeletions among 112 cases of Sotos syndrome: low copy repeats possibly mediate the common deletion. Human Mutation 22: 378–387.

Kurotaki N, Harada N, Yoshiura K et al. (2001) Molecular characterization of NSD1, a human homologue of the mouse Nsd1 gene. Gene 279: 197–204.

Kurotaki N, Imaizumi K, Harada N et al. (2002) Haploinsufficiency of NSD1 causes Sotos syndrome. Nature Genetics 30: 365–366.

Kurotaki N, Shen JJ, Touyama M et al. (2005) Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genetics in Medicine 7: 479–483.

Melchior L, Schwartz M and Duno M (2005) dHPLC screening of the NSD1 gene identifies nine novel mutations – summary of the first 100 Sotos syndrome mutations. Annals of Human Genetics 69: 222–226.

Miyake N, Kurotaki N, Sugawara H et al. (2003) Preferential paternal origin of microdeletions caused by prezygotic chromosome or chromatid rearrangements in Sotos syndrome. American Journal of Human Genetics 72: 1331–1337.

Mochizuki J, Saitsu H, Mizuguchi T et al. (2008) Alu‐related 5q35 microdeletions in Sotos syndrome. Clinical Genetics 74: 384–391.

Mouridsen SE and Hansen MB (2002) Neuropsychiatric aspects of Sotos syndrome. A review and two case illustrations. European Child & Adolescent Psychiatry 11: 43–48.

Nagai T, Matsumoto N, Kurotaki N et al. (2003) Sotos syndrome and haploinsufficiency of NSD1: clinical features of intragenic mutations and submicroscopic deletions. Journal of Medical Genetics 40: 285–289.

Nielsen AL, Jorgensen P, Lerouge T et al. (2004) Nizp1, a novel multitype zinc finger protein that interacts with the NSD1 histone lysine methyltransferase through a unique C2HR motif. Molecular and Cellular Biology 24: 5184–5196.

Opitz JM, Weaver DW and Reynolds JF Jr (1998) The syndromes of Sotos and Weaver: reports and review. American Journal of Medical Genetics 79: 294–304.

Rahman N (2005) Mechanisms predisposing to childhood overgrowth and cancer. Current Opinion in Genetics & Development 15: 227–233.

Rayasam GV, Wendling O, Angrand PO et al. (2003) NSD1 is essential for early post‐implantation development and has a catalytically active SET domain. EMBO Journal 22: 3153–3163.

Rio M, Clech L, Amiel J et al. (2003) Spectrum of NSD1 mutations in Sotos and Weaver syndromes. Journal of Medical Genetics 40: 436–440.

Rosati R, La Starza R, Veronese A et al. (2002) NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 99: 3857–3860.

Saugier‐Veber P, Bonnet C, Afenjar A et al. (2007) Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome. Human Mutation 28: 1098–1107.

Schaefer GB, Bodensteiner JB, Buehler BA et al. (1997) The neuroimaging findings in Sotos syndrome. American Journal of Medical Genetics 68: 462–465.

Schaft D, Roguev A, Kotovic KM et al. (2003) The histone 3 lysine 36 methyltransferase, SET2, is involved in transcriptional elongation. Nucleic Acids Research 31: 2475–2482.

Sosonkina N, Miyake N, Harada N et al. (2007) Less frequent NSD1‐intragenic deletions in Japanese Sotos syndrome: analysis of 30 patients by NDS1‐exon array CGH, quantitative fluorescent duplex PCR, and fluorescence in situ hybridization. Acta Medica Nagasakiensia 52: 29–34.

Sotos JF, Dodge PR, Muirhead D et al. (1964) Cerebral gigantism in childhood. a syndrome of excessively rapid growth and acromegalic features and a nonprogressive neurologic disorder. New England Journal of Medicine 271: 109–116.

Stec I, Nagl SB, van Ommen GJ et al. (2000) The PWWP domain: a potential protein‐protein interaction domain in nuclear proteins influencing differentiation. FEBS Letter 473: 1–5.

Stec I, Wright TJ, van Ommen GJ et al. (1998) WHSC1, a 90 kb SET domain‐containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf‐Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. Human Molecular Genetics 7: 1071–1082.

Tatton‐Brown K, Douglas J, Coleman K et al. (2005a) Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome. Journal of Medical Genetics 42: 307–313.

Tatton‐Brown K, Douglas J, Coleman K et al. (2005b) Genotype‐phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. American Journal of Human Genetics 77: 193–204.

Tatton‐Brown K and Rahman N (2004) Clinical features of NSD1‐positive Sotos syndrome. Clinical Dysmorphology 13: 199–204.

Tatton‐Brown K and Rahman N (2007) Sotos syndrome. European Journal of Human Genetics 15: 264–271.

Tei S, Tsuneishi S and Matsuo M (2006) The first Japanese familial Sotos syndrome with a novel mutation of the NSD1 gene. Kobe Journal of Medical Science 52: 1–8.

Turkmen S, Gillessen‐Kaesbach G, Meinecke P et al. (2003) Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes. European Journal of Human Genetics 11: 858–865.

Visser R, Shimokawa O, Harada N et al. (2005a) Identification of a 3.0‐kb major recombination hotspot in patients with Sotos syndrome who carry a common 1.9‐Mb microdeletion. American Journal of Human Genetics 76: 52–67.

Visser R, Shimokawa O, Harada N et al. (2005b) Non‐hotspot‐related breakpoints of common deletions in Sotos syndrome are located within destabilised DNA regions. Journal of Medical Genetics 42: e66.

Waggoner DJ, Raca G, Welch K et al. (2005) NSD1 analysis for Sotos syndrome: insights and perspectives from the clinical laboratory. Genetics in Medicine 7: 524–533.

Wang GG, Cai L, Pasillas MP et al. (2007) NUP98‐NSD1 links H3K36 methylation to Hox‐A gene activation and leukaemogenesis. Nature Cell Biology 9: 804–812.

Weaver DD, Graham CB, Thomas IT et al. (1974) A new overgrowth syndrome with accelerated skeletal maturation, unusual facies, and camptodactyly. Journal of Pediatrics 84: 547–552.

Yamada‐Okabe T and Matsumoto N (2008) Decreased serum dependence in the growth of NIH3T3 cells from the overexpression of human nuclear receptor‐binding SET‐domain‐containing protein 1 (NSD1) or fission yeast su(var)3‐9, enhancer‐of‐zeste, trithorax 2 (SET2). Cell Biochemistry and Function 26: 146–150.

Zhao Z, Yu Y, Meyer D et al. (2005) Prevention of early flowering by expression of FLOWERING LOCUS C requires methylation of histone H3 K36. Nature Cell Biology 7: 1256–1260.

Further Reading

Kurotaki N and Matsumoto N (2006) Sotos syndrome. In: Lupski JR and Stankiewicz P (eds) Genomic Disorders: The Genomic Basis of Disease, pp. 237–246. Totowa: Humana Press.

Kurotaki N, Stankiewicz P, Wakui K et al. (2005) Sotos syndrome common deletion is mediated by directly oriented subunits within inverted Sos‐REP low‐copy repeats. Human Molecular Genetics 14: 535–542.

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How to Cite close
Niikawa, Norio, Miyake, Noriko, and Matsumoto, Naomichi(Dec 2008) Sotos Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021430]