NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes Jenny Douglas,

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NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes Jenny Douglas, Sandra Hanks, I. Karen Temple, Sally Davies, Alexandra Murray, Meena Upadhyaya, Susan Tomkins, Helen E. Hughes, R.P. Trevor Cole, Nazneen Rahman The American Journal of Human Genetics Volume 72, Issue 1, Pages 132-143 (January 2003) DOI: 10.1086/345647 Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 1 Typical facial phenotype in overgrowth groups 1, 2, and 3. A, Group 1 (classic facial gestalt of Sotos syndrome). B, Group 2 (patients with similarities to Sotos syndrome but with some atypical characteristics; primarily the facial features were not classical). C, Group 3 (Weaver syndrome). Patients in Group 4 did not have a distinctive facial phenotype but were characterized by not having the facial phenotypes present in the other three groups. The American Journal of Human Genetics 2003 72, 132-143DOI: (10.1086/345647) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 2 NSD1 deletions in three patients with childhood overgrowth—COG25, COG44, and COG70. A, Marker allele haplotypes for nine microsatellite markers spanning NSD1, demonstrating maternal deletion in COG25, probable paternal deletion in COG44, and deletion of unknown origin in COG70. B, Fluorescent multiplex PCR demonstrating a 0.5 reduction of NSD1 exons relative to MLH1, in COG25, COG44, and COG70, and a normal ratio in two control samples: (1) the mother of COG25 and (2) COG33 (who has an intragenic NSD1 mutation). The Y-axis shows fluorescence (in arbitrary units), and the X-axis indicates the size (in bp). The American Journal of Human Genetics 2003 72, 132-143DOI: (10.1086/345647) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 3 Schematic representation of NSD1, showing the distribution of intragenic mutations identified in the present study and the associated phenotype. Exons of NSD1 are shown as boxes with the exon number underneath. Functional domains of NSD1 are shown as shaded boxes, with the domain name above. Mutations are shown as triangles, with truncating mutations (insertions, deletions, nonsense, and splice-site) above the gene and missense mutations below the gene. One mutation (R604X) was identified twice and is depicted as two triangles, one above the other. The American Journal of Human Genetics 2003 72, 132-143DOI: (10.1086/345647) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 4 NSD1 missense mutations in patients with childhood overgrowth. Residues altered by missense mutations are shown in red boxes. Consensus residues in the PHD and SAC domains are shown in black boxes. Conserved residues in NSD1, mouse Nsd1, NSD2, and NSD3 are shown in shaded boxes. A, The alignment of five PHD domains in NSD1 and the position of the missense mutations identified in the present study. B, Missense mutations in PWWPII, SAC, SET, and C/H-rich domains and in corresponding regions in mouse Nsd1, NSD2, and NSD3. The American Journal of Human Genetics 2003 72, 132-143DOI: (10.1086/345647) Copyright © 2003 The American Society of Human Genetics Terms and Conditions