Spectrum of detected genetic variants in NSD1 gene in Patients with Sotos syndrome

Sotos syndrome is a rare autosomal dominant disorder with an incidence of about 1 in 14,000 newborns. Despite a number of characteristic clinical manifestations, its diagnosis is difficult due to the high degree of overlap of the phenotype with a number of other hereditary syndromes, such as Beckwith-Wiedemann syndrome or Marfan syndrome. The molecular genetic cause of Sotos syndrome is mutations in the NSD1 gene, leading to protein dysfunction. The article presents and characterizes variants in the NSD1 gene found during diagnostics using high-throughput sequencing (NGS) and MLPA.

Sotos syndrome, NSD1, NGS, MLPA

1. Asadi S. The Role of Mutations on Genes NSD1 and NFIX, In Sotos Syndrome. Clinical Research in Neurology. 2020;3(1):1-4.

2. Tatton-Brown K., Cole T.R.P., Rahman N. Sotos Syndrome. 2004 Dec 17 [updated 2019 Aug 1]. In: Adam M.P., Ardinger H.H., Pagon R.A., Wallace S.E., Bean L.J.H., Mirzaa G., Amemiya A., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. PMID: 20301652.

3. Douglas J., Hanks S., Temple I.K., Davies S., Murray A., Upadhyaya M., Tomkins S., Hughes H.E., Cole T.R., Rahman N. NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. Am J Hum Genet. 2003 Jan;72(1):132-43. doi: 10.1086/345647.

4. Kurotaki N., Harada N., Yoshiura K., Sugano S., Niikawa N., Matsumoto N. Molecular characterization of NSD1, a human homologue of the mouse Nsd1 gene. Gene. 2001 Nov 28;279(2):197-204. doi: 10.1016/s0378-1119(01)00750-8.

5. Huang N., vom Baur E., Garnier J.M., Lerouge T., Vonesch J.L., Lutz Y., Chambon P., Losson R. Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators. EMBO J. 1998 Jun 15;17(12):3398-412. doi: 10.1093/emboj/17.12.3398.

6. Rona G.B., Eleutherio E.C.A., Pinheiro A.S. PWWP domains and their modes of sensing DNA and histone methylated lysines. Biophys Rev. 2016 Mar;8(1):63-74. doi: 10.1007/s12551-015-0190-6.

7. Dillon S.C., Zhang X., Trievel R.C., Cheng X. The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol. 2005;6(8):227. doi: 10.1186/gb-2005-6-8-227.

8. Capili A.D., Schultz D.C., Rauscher III F.J., Borden K.L. Solution structure of the PHD domain from the KAP-1 corepressor: structural determinants for PHD, RING and LIM zinc-binding domains. EMBO J. 2001 Jan 15;20(1-2):165-77. doi: 10.1093/emboj/20.1.165.

9. Lucio-Eterovic A.K., Singh M.M., Gardner J.E., Veerappan C.S., Rice J.C., Carpenter P.B. Role for the nuclear receptor-binding SET domain protein 1 (NSD1) methyltransferase in coordinating lysine 36 methylation at histone 3 with RNA polymerase II function. Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16952-7. doi: 10.1073/pnas.1002653107.

10. Tauchmann S., Schwaller J. NSD1: A Lysine Methyltransferase between Developmental Disorders and Cancer. Life (Basel). 2021 Aug 25;11(9):877. doi: 10.3390/life11090877.

11. Türkmen S., Gillessen-Kaesbach G., Meinecke P., Albrecht B., Neumann L.M., Hesse V., Palanduz S., Balg S., Majewski F., Fuchs S., Zschieschang P., Greiwe M., Mennicke K., Kreuz F.R., Dehmel H.J., Rodeck B., Kunze J., Tinschert S., Mundlos S., Horn D. Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes. Eur J Hum Genet. 2003 Nov;11(11):858-65. doi: 10.1038/sj.ejhg.5201050.

12. Dikow N., Maas B., Gaspar H., Kreiss-Nachtsheim M., Engels H., Kuechler A., Garbes L., Netzer C., Neuhann T.M., Koehler U., Casteels K., Devriendt K., Janssen J.W., Jauch A., Hinderhofer K., Moog U. The phenotypic spectrum of duplication 5q35.2-q35.3 encompassing NSD1: is it really a reversed Sotos syndrome? Am J Med Genet A. 2013 Sep;161A(9):2158-66. doi: 10.1002/ajmg.a.36046.

13. Bernhardt I.T., Gunn A.J., Carter P.J. Growth hormone treatment for short stature associated with duplication of the NSD1 Sotos syndrome gene. Endocrinol Diabetes Metab Case Rep. 2021 Mar 5;2021:20-0033. doi: 10.1530/EDM-20-0033.

14. Zhao Q., Caballero O.L., Levy S., Stevenson B.J., Iseli C., de Souza S.J., Galante P.A., Busam D., Leversha M.A., Chadalavada K., Rogers Y.H., Venter J.C., Simpson A.J., Strausberg R.L. Transcriptome-guided characterization of genomic rearrangements in a breast cancer cell line. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1886-91. doi: 10.1073/pnas.0812945106.

15. Wang G.G., Cai L., Pasillas M.P., Kamps M.P. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol. 2007 Jul;9(7):804-12. doi: 10.1038/ncb1608.

16. Berdasco M., Ropero S., Setien F., Fraga M.F., Lapunzina P., Losson R., Alaminos M., Cheung N.K., Rahman N., Esteller M. Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma. Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21830-5. doi: 10.1073/pnas.0906831106.

17. Faravelli F. NSD1 mutations in Sotos syndrome. Am J Med Genet C Semin Med Genet. 2005 Aug 15;137C(1):24-31. doi: 10.1002/ajmg.c.30061.

18. Visser R., Shimokawa O., Harada N., Niikawa N., Matsumoto N. Non-hotspot-related breakpoints of common deletions in Sotos syndrome are located within destabilised DNA regions. J Med Genet. 2005 Nov;42(11):e66. doi: 10.1136/jmg.2005.034355.

19. Waggoner D.J., Raca G., Welch K., Dempsey M., Anderes E., Ostrovnaya I., Alkhateeb A., Kamimura J., Matsumoto N., Schaeffer G.B., Martin C.L., Das S. NSD1 analysis for Sotos syndrome: insights and perspectives from the clinical laboratory. Genet Med. 2005 Oct;7(8):524-33. doi: 10.1097/01.GIM.0000178503.15559.d3.

20. Рыжкова О.П., Кардымон О.Л., Прохорчук Е.Б., Коновалов Ф.А., Масленников А.Б., Степанов В.А., Афанасьев А.А., Заклязьминская Е.В., Ребриков Д.В., Савостьянов К.В., Глотов А.С., Костарева А.А., Павлов А.Е., Голубенко М.В., Поляков А.В., Куцев С.И. Руководство по интерпретации данных последовательности ДНК человека, полученных методами массового параллельного секвенирования (MPS) (редакция 2018, версия 2). Медицинская генетика. 2019;18(2):3-23