BACKGROUND: Most cases of Sotos syndrome are caused by intragenic NSD1 mutations or 5q35 microdeletions. It is uncertain whether allelic or genetic heterogeneity underlies the residual cases and it has been proposed that other mechanisms, such as 11p15 defects, might be responsible for Sotos cases without NSD1 mutations or 5q35 microdeletions. OBJECTIVE: To develop a multiplex ligation dependent probe amplification (MLPA) assay to screen NSD1 for exonic deletions/duplications. METHODS: Analysis was undertaken of 18 classic Sotos syndrome cases in which NSD1 mutations and 5q35 microdeletions were excluded. Long range polymerase chain reaction (PCR) was used to characterise the mechanism of generation of the partial NSD1 deletions. RESULTS: Eight unique partial NSD1 deletions were identified: exons 1-2 (n = 4), exons 3-5, exons 9-13, exons 19-21, and exon 22. Using long range PCR six of the deletions were confirmed and the precise breakpoints in five cases characterised. This showed that three had arisen through Alu-Alu recombination and two from non-homologous end joining. CONCLUSIONS: MLPA is a robust, inexpensive, simple technique that reliably detects both 5q35 microdeletions and partial NSD1 deletions that together account for approximately 15% of Sotos syndrome.
BACKGROUND: Most cases of Sotos syndrome are caused by intragenic NSD1 mutations or 5q35 microdeletions. It is uncertain whether allelic or genetic heterogeneity underlies the residual cases and it has been proposed that other mechanisms, such as 11p15 defects, might be responsible for Sotos cases without NSD1 mutations or 5q35 microdeletions. OBJECTIVE: To develop a multiplex ligation dependent probe amplification (MLPA) assay to screen NSD1 for exonic deletions/duplications. METHODS: Analysis was undertaken of 18 classic Sotos syndrome cases in which NSD1 mutations and 5q35 microdeletions were excluded. Long range polymerase chain reaction (PCR) was used to characterise the mechanism of generation of the partial NSD1 deletions. RESULTS: Eight unique partial NSD1 deletions were identified: exons 1-2 (n = 4), exons 3-5, exons 9-13, exons 19-21, and exon 22. Using long range PCR six of the deletions were confirmed and the precise breakpoints in five cases characterised. This showed that three had arisen through Alu-Alu recombination and two from non-homologous end joining. CONCLUSIONS: MLPA is a robust, inexpensive, simple technique that reliably detects both 5q35 microdeletions and partial NSD1 deletions that together account for approximately 15% of Sotos syndrome.
Authors: Katheryn Grand; Christina Gonzalez-Gandolfi; Amanda M Ackermann; Deema Aljeaid; Emma Bedoukian; Lynne M Bird; Diva D De Leon; Jullianne Diaz; Robert J Hopkin; Sejal P Kadakia; Beth Keena; Karen O Klein; Ian Krantz; Eyby Leon; Katherine Lord; Carey McDougall; Livija Medne; Cara M Skraban; Charles A Stanley; Jennifer Tarpinian; Elaine Zackai; Matthew A Deardorff; Jennifer M Kalish Journal: Am J Med Genet A Date: 2019-02-04 Impact factor: 2.802
Authors: Gustavo H Vieira; Melissa M Cook; Renata L Ferreira De Lima; Carlos E Frigério Domingues; Daniel R de Carvalho; Isaias Soares de Paiva; Danilo Moretti-Ferreira; Anand K Srivastava Journal: Mol Syndromol Date: 2015-01-21
Authors: Benjamin Kamien; Anne Ronan; Gemma Poke; Ingrid Sinnerbrink; Gareth Baynam; Michelle Ward; William T Gibson; Tracy Dudding-Byth; Rodney J Scott Journal: Mol Syndromol Date: 2018-01-25
Authors: Mariana R Botton; Xingwu Lu; Geping Zhao; Elena Repnikova; Yoshinori Seki; Andrea Gaedigk; Eric E Schadt; Lisa Edelmann; Stuart A Scott Journal: Hum Mutat Date: 2019-11 Impact factor: 4.878
Authors: J A Rosenfeld; K H Kim; B Angle; R Troxell; J L Gorski; M Westemeyer; M Frydman; Y Senturias; D Earl; B Torchia; R A Schultz; J W Ellison; K Tsuchiya; S Zimmerman; T A Smolarek; B C Ballif; L G Shaffer Journal: Mol Syndromol Date: 2013-01-05